Piperidino-dihydrothienopyrimidine sulfoxides and their use for treating COPD and asthma

ABSTRACT

The invention relates to novel piperidino-dihydrothienopyrimidine sulfoxides of formula I, 
                         
wherein Ring A is a 6-membered aromatic ring which may optionally comprise one or two nitrogen atoms and
 
wherein R is Cl and
 
wherein R may be located either in the para-, meta- or ortho-position of Ring A,
 
wherein S* is a sulphur atom that represents a chiral center,
 
and all pharmaceutically acceptable salts, enantiomers and racemates, hydrates and solvates thereof and the use of these compounds for the treatment of inflammatory or allergic diseases of the respiratory tract such as COPD or asthma.

The invention relates to novel piperidino-dihydrothienopyrimidinesulfoxides of formula I,

wherein Ring A is a 6-membered aromatic ring which may optionallycomprise one or two nitrogen atoms andwherein R is Cl andwherein R may be located either in the para-, meta- or ortho-position ofRing A,wherein S* is a sulphur atom that represents a chiral center,and all pharmaceutically acceptable salts, enantiomers and racemates,hydrates and solvates thereof and the use of these compounds for thetreatment of inflammatory or allergic diseases of the respiratory tractsuch as COPD or asthma.

1 PRIOR ART

WO 2006/111549 and WO 2007/118793 each disclosedihydrothieno-pyrimidinesulfoxides which are substituted by piperazineinstead of piperidine. WO 2009/050248 disclosespiperidino-dihydrothienopyrimidines which differ from the compounds ofthe invention in their substitution pattern. Due to their particularsubstitution pattern the compounds of the invention are at the same timemore potent PDE4 inhibitors than the compounds disclosed in WO2009/050248 and show a minimized potential for the development ofunwanted gastrointestinal side effects.

2 DESCRIPTION OF THE INVENTION

Surprisingly it has been found that the compounds of the invention aredue to their particular substitution pattern particularly suitable forthe treatment of inflammatory disease. The compounds of the inventionare further superior to the correspondingpiperazino-dihydrothienopyrimidine sulfoxides of the prior art documentWO 2009/050248.

The present invention therefore relates to compounds of formula I

wherein Ring A is a 6-membered aromatic ring which may optionallycomprise one or two nitrogen atoms andwherein R is Cl andwherein R may be located either in the para-, meta- or ortho-position ofRing A,wherein S* represents a sulphur atom that is a chiral center,and all pharmaceutically acceptable salts thereof, enantiomers andracemates thereof, hydrates, solvates and polymorphs thereof.

The invention further relates to the above-mentioned compounds offormula I, wherein R is Cl and wherein R is preferably located in thepara-position of Ring A, and all pharmaceutically acceptable saltsthereof, enantiomers and racemates thereof, hydrates, solvates andpolymorphs thereof.

The invention further relates to the above-mentioned compounds offormula I, wherein Ring A is selected from the group consisting ofphenyl, pyridinyl and pyrimidinyl, and all pharmaceutically acceptablesalts thereof, enantiomers and racemates thereof, hydrates, solvates andpolymorphs thereof. The invention preferably relates to theabove-mentioned compounds of formula I, wherein Ring A is selected fromthe group consisting of phenyl, pyridinyl and pyrimidinyl and wherein Ris a Cl-substituent in the para-position, and all pharmaceuticallyacceptable salts thereof, enantiomers and racemates thereof, hydrates,solvates and polymorphs thereof.

In particular the invention concerns the compound of formula II,

and all pharmaceutically acceptable salts thereof, enantiomers andracemates thereof, hydrates, solvates and polymorphs thereof.

In particular the invention concerns the compound of formula III,

and all pharmaceutically acceptable salts thereof, enantiomers andracemates thereof, hydrates, solvates and polymorphs thereof.

The invention further relates to the above-mentioned compounds accordingof one of formula I, II or III, wherein S* represents a sulphur atomwhich represents a chiral center being in the R-configuration.

The invention further relates to the above-mentioned compounds accordingof one of formula I, II or III, wherein S* represents a sulphur atomwhich represents a chiral center being in the S-configuration.

For the compound of formula III three different polymorphs, twodifferent anhydrous forms and one dihydrate form have been identifiedand characterized by X-ray powder diffraction (XRPD), bythermogravimetric analysis (TGA) and by differential scanningcalorimetry (DSC).

FIG. 3 a shows the X-ray powder diffraction diagram of the anhydrousform A of formula III (see Example 2). In this XRPD diagram of theanhydrous form A of formula III the following the 2•-values and d-valuescould be observed (Table 1).

TABLE 1 All observable peaks for the anhydrate Form A: 2-Theta d(Å) l/lo4.48 19.70 27 8.76 10.09 46 9.54 9.26 11 12.98 6.82 69 13.44 6.58 915.50 5.71 2 16.56 5.35 8 17.94 4.94 35 18.54 4.78 20 19.18 4.62 10020.36 4.36 15 20.64 4.30 10 21.48 4.13 23 22.62 3.93 38 22.98 3.87 1523.65 3.76 4 24.46 3.64 15 24.76 3.59 21 26.61 3.35 5 27.34 3.26 1327.92 3.19 28 29.14 3.06 15 30.68 2.91 11 31.05 2.88 17 32.34 2.77 832.65 2.74 3 33.28 2.69 20 33.54 2.67 17

The major peaks of the XRPD diagram of anhydrous Form A of the compoundof formula III are listed in Table 2.

TABLE 2 Major peaks for the anhydrate Form A: 2-Theta d(Å) l/lo 4.4819.70 27 8.76 10.09 46 12.98 6.82 69 17.94 4.94 35 19.18 4.62 100 21.484.13 23 22.62 3.93 38 24.76 3.59 21 27.92 3.19 28

The most prominent peaks of the XRPD diagram of anhydrous Form A of thecompound of formula III are listed in Table 3.

TABLE 3 Prominent peaks for the anhydrate Form A: 2-Theta d(Å) l/lo 8.7610.09 46 12.98 6.82 69 19.18 4.62 100

FIG. 3 b shows the X-ray powder diffraction diagram of the anhydrousform B of formula III (see Example 2). In this XRPD diagram of theanhydrous form B of formula III the following 2•-values and d-valuescould be observed (Table 4).

TABLE 4 All observable peaks for the anhydrate Form B: 2-Theta d(Å) l/lo4.78 18.47 46 9.78 9.04 25 14.56 6.08 5 15.14 5.85 17 16.96 5.22 4317.48 5.07 14 19.18 4.62 100 19.74 4.49 41 20.80 4.27 38 21.30 4.17 7121.72 4.09 28 23.82 3.73 50 24.28 3.66 55 24.58 3.62 35 25.53 3.49 426.64 3.34 21 27.12 3.29 2 27.61 3.23 13 27.90 3.20 31 28.48 3.13 828.78 3.10 18 29.74 3.00 8 30.92 2.89 18 31.75 2.82 6 32.04 2.79 1032.78 2.73 2 34.55 2.59 8

The major peaks of the XRPD diagram of anhydrous Form B of the compoundof formula III are listed in Table 5.

TABLE 5 Major peaks for the anhydrate Form B: 2-Theta d(Å) l/lo 4.7818.47 46 9.78 9.04 25 15.14 5.85 17 16.96 5.22 43 19.18 4.62 100 19.744.49 41 20.80 4.27 38 21.30 4.17 71 21.72 4.09 28 23.82 3.73 50 24.283.66 55 27.90 3.20 31

The most prominent peaks of the XRPD diagram of anhydrous Form B of thecompound of formula III are listed in Table 6.

TABLE 6 Prominent peaks for the anhydrate Form B 2-Theta d(Å) l/lo 4.7818.47 46 16.96 5.22 43 19.18 4.62 100 21.30 4.17 71 24.28 3.66 55 23.823.73 50

Consequently the invention concerns a crystalline anhydrous compound offormula III which shows a reflex peak in the X-ray powder diffractiondiagram with a d-value of 4.62 Å.

Further the invention concerns a crystalline anhydrous compound offormula III which shows reflex peaks in the X-ray powder diffractiondiagram with d-values of 4.62 Å, 6.82 Å and 10.09 Å.

Further the invention concerns a crystalline anhydrous compound offormula III, which shows reflex peaks in the X-ray powder diffractiondiagram with d-values of 4.62 Å, 4.17 Å and 3.66 Å.

Additionally the invention relates to a crystalline anhydrous compoundof formula III, which shows reflex peaks in the X-ray powder diffractiondiagram with d-values of 4.62 Å, 6.82 Å, 10.09 Å, 3.93 Å and 4.94 Å.

Additionally the invention relates to a crystalline anhydrous compoundof formula III, which shows reflex peaks in the X-ray powder diffractiondiagram with d-values of 4.62 Å, 4.17 Å, 3.66 Å, 3.73 Å and 18.47 Å.

FIG. 3 c shows the X-ray powder diffraction diagram of the dihydrateform C of formula III (see Example 2). In this XRPD diagram of thedihydrate form C of formula III the following 2•-values and d-valuescould be observed (Table 7).

TABLE 7 All observable peaks for the dihydrate Form C: 2-Theta d(Å) l/lo8.60 10.27 4 9.78 9.04 15 10.28 8.60 28 11.10 7.97 6 12.96 6.83 8 13.726.45 16 14.72 6.01 5 15.46 5.73 9 17.20 5.15 70 18.72 4.74 21 19.10 4.6429 19.70 4.50 33 20.04 4.43 26 20.70 4.29 75 21.54 4.12 100 22.48 3.9561 23.00 3.86 5 23.78 3.74 5 24.26 3.67 7 24.62 3.61 15 24.98 3.56 1926.50 3.36 41 27.92 3.19 8 28.62 3.12 20 29.21 3.05 9 29.64 3.01 1530.18 2.96 19 30.66 2.91 16 31.88 2.80 4 33.00 2.71 12 33.94 2.64 9

The major peaks of the XRPD diagram of dihydrate Form C of the compoundof formula III are listed in Table 8.

TABLE 8 Major peaks for the dihydrate Form C: 2-Theta d(Å) l/lo 10.288.60 28 17.20 5.15 70 18.72 4.74 21 19.10 4.64 29 19.70 4.50 33 20.044.43 26 20.70 4.29 75 21.54 4.12 100 22.48 3.95 61 26.50 3.36 41 28.623.12 20

The most prominent peaks of the XRPD diagram of dihydrate Form C of thecompound of formula III are listed in Table 9.

TABLE 9 Prominent peaks for the dihydrate Form C: 2-Theta d(Å) l/lo17.20 5.15 70 20.70 4.29 75 21.54 4.12 100 22.48 3.95 61 26.50 3.36 41

Consequently, the invention relates to a crystalline dihydrate compoundof formula III, which shows a reflex peak in the X-ray powderdiffraction diagram with a d-value of 4.12 Å.

The invention also relates to a crystalline dihydrate compound offormula III, which shows reflex peaks in the X-ray powder diffractiondiagram with d-values of 4.12 Å, 4.29 Å and 5.15 Å.

The invention further relates to a crystalline dihydrate compound offormula III, which shows reflex peaks in the X-ray powder diffractiondiagram with d-values of 4.12 Å, 4.29 Å, 5.15 Å, 3.95 Å and 3.36 Å.

In another aspect the invention relates to the above-mentioned compoundsfor use as a medicament.

Another aspect of the invention concerns a method of treating a diseasewhich can be treated by the inhibition of the PDE4-enzyme comprising thestep of administering one of the aforementioned compounds according toat least one of formulas I, II or III to a patient in need thereof.

Further the invention concerns the use of one of the aforementionedcompounds according to at least one of formulas I, II or III forpreparing a medicament for the treatment and/or prevention of a diseasewhich can be treated by the inhibition of the PDE4-enzyme.

Further the invention concerns one of the aforementioned compoundsaccording to at least one of formulas I, II or III for the treatmentand/or prevention of a disease which can be treated by the inhibition ofthe PDE4-enzyme.

The invention further relates to the above-mentioned method of treatinga disease which can be treated by the inhibition of the PDE4-enzymecomprising the step of administering one of the aforementioned compoundsaccording to at least one of formulas I, II or III to a patient in needthereof, characterised in that the disease to be treated is selectedfrom the group consisting of a respiratory disease, a gastrointestinaldisease, an inflammatory disease of the joints, the skin or the eyes,cancer and a disease of the peripheral or central nervous system.

Further the invention concerns the use of one of the aforementionedcompounds according to at least one of formulas I, II or III forpreparing a medicament for the treatment and/or prevention of a diseasewhich can be treated by the inhibition of the PDE4-enzyme, wherein thedisease to be treated is selected from the group consisting of arespiratory disease, a gastrointestinal disease, an inflammatory diseaseof the joints, the skin or the eyes, cancer and a disease of theperipheral or central nervous system.

Further the invention concerns one of the aforementioned compoundsaccording to at least one of formulas I, II or III for the treatmentand/or prevention of a disease which can be treated by the inhibition ofthe PDE4-enzyme, wherein the disease to be treated is selected from thegroup consisting of a respiratory disease, a gastrointestinal disease,an inflammatory disease of the joints, the skin or the eyes, cancer anda disease of the peripheral or central nervous system.

The invention further relates to the above-mentioned method of treatinga disease which is selected from the group consisting of a respiratoryor pulmonary disease which is accompanied by increased mucus production,inflammations and/or obstructive diseases of the respiratory tract,comprising the step of administering one of the aforementioned compoundsaccording to at least one of formulas I, II or III to a patient in needthereof.

Further the invention concerns the use of one of the aforementionedcompounds according to at least one of formulas I, II or III forpreparing a medicament for the treatment and/or prevention of a diseaseselected from the group consisting of a respiratory or pulmonary diseasewhich is accompanied by increased mucus production, inflammations and/orobstructive diseases of the respiratory tract, comprising the step ofadministering one of the aforementioned compounds according to at leastone of formulas I, II or III to a patient in need thereof.

Further the invention concerns one of the aforementioned compoundsaccording to at least one of formulas I, II or III for the treatmentand/or prevention of a disease selected from the group consisting of arespiratory or pulmonary disease which is accompanied by increased mucusproduction, inflammations and/or obstructive diseases of the respiratorytract, comprising the step of administering one of the aforementionedcompounds according to at least one of formulas I, II or II.

The invention further relates to the above-mentioned method of treatinga disease which is selected from the group consisting of COPD, chronicsinusitis, idiopathic pulmonary fibrosis, alpha 1 antitrypsindeficiency, asthma and chronic bronchitis, comprising the step ofadministering one of the aforementioned compounds according to at leastone of formulas I, II or III to a patient in need thereof.

Further the invention concerns the use of one of the aforementionedcompounds according to at least one of formulas I, II or III forpreparing a medicament for the treatment and/or prevention of a diseaseselected from the group consisting of COPD, chronic sinusitis,idiopathic pulmonary fibrosis, alpha 1 antitrypsin deficiency, asthmaand chronic bronchitis.

Further the invention concerns one of the aforementioned compoundsaccording to at least one of formulas I, II or III for the treatmentand/or prevention of a disease selected from the group consisting ofCOPD, chronic sinusitis, idiopathic pulmonary fibrosis, alpha 1antitrypsin deficiency, asthma and chronic bronchitis.

Further the invention concerns the use of one of the aforementionedcompounds according to at least one of formulas I, II or III forpreparing a medicament for the treatment and/or prevention of a diseaseselected from the group consisting of rheumatoid arthritis, sarcoidosis,glaucoma and the dry eyes syndrome.

Further the invention concerns one of the aforementioned compoundsaccording to at least one of formulas I, II or III for the treatmentand/or prevention of a disease selected from the group consisting ofrheumatoid arthritis, sarcoidosis, glaucoma and the dry eyes syndrome.

The invention further relates to the above-mentioned method of treatinga disease which is selected from the group consisting of Crohn's diseaseand ulcerative colitis, comprising the step of administering one of theaforementioned compounds according to at least one of formulas I, II orIII to a patient in need thereof.

Further the invention concerns the use of one of the aforementionedcompounds according to at least one of formulas I, II or III forpreparing a medicament for the treatment and/or prevention of a diseaseselected from the group consisting of Crohn's disease and ulcerativecolitis.

Further the invention concerns one of the aforementioned compoundsaccording to at least one of formulas I, II or III for the treatmentand/or prevention of a disease selected from the group consisting ofCrohn's disease and ulcerative colitis.

The invention further relates to the above-mentioned method of treatinga disease which is selected from the group consisting of depression,bipolar or manic depression, acute and chronic anxiety states,schizophrenia, Alzheimer's disease, Parkinson's disease, acute andchronic multiple sclerosis or acute and chronic pain and brain damagecaused by stroke, hypoxia or cranio-cerebral trauma, comprising the stepof administering one of the aforementioned compounds according to atleast one of formulas I, II or III to a patient in need thereof.

Further the invention concerns the use of one of the aforementionedcompounds according to at least one of formulas I, II or III forpreparing a medicament for the treatment and/or prevention of a diseaseselected from the group consisting of depression, bipolar or manicdepression, acute and chronic anxiety states, schizophrenia, Alzheimer'sdisease, Parkinson's disease, acute and chronic multiple sclerosis oracute and chronic pain and brain damage caused by stroke, hypoxia orcranio-cerebral trauma.

Further the invention concerns one of the aforementioned compoundsaccording to at least one of formulas I, II or III for the treatmentand/or prevention of a disease selected from the group consisting ofdepression, bipolar or manic depression, acute and chronic anxietystates, schizophrenia, Alzheimer's disease, Parkinson's disease, acuteand chronic multiple sclerosis or acute and chronic pain and braindamage caused by stroke, hypoxia or cranio-cerebral trauma.

In another aspect the invention concerns a pharmaceutical compositioncomprising at least one of the aforementioned compounds according to atleast one of formulas I, II or III.

In a further aspect the invention relates to a pharmaceuticalcomposition characterised in that it contains at least one of theaforementioned compounds of at least one of formulas I, II or III incombination with one or more active substances selected from the groupconsisting of betamimetics, corticosteroids, anticholinergics, otherPDE4 inhibitors, NSAIDS, COX2 inhibitors, EP4 receptor antagonists,EGFR-inhibitors, LTD4-antagonists, CCR3-inhibitors, iNOS-inhibitors,MRP4-inhibitors and SYK inhibitors.

In another aspect the invention relates to a method of manufacturing thecompound A

wherein HX is a pharmaceutically acceptable acid,comprising the steps a) and b), wherein instep a) compound B

wherein HY is a pharmaceutically acceptable acid,is reduced by borane and wherein instep b) a pharmaceutically acceptable acid HX is added in order toobtain compound A.

In one embodiment of the above-mentioned method of manufacturingcompound A the borane for the reduction in step a) is added directly.

In another embodiment of the above-mentioned method of manufacturingcompound A the borane for the reduction in step a) is generated in-situ.

In a preferred embodiment of the above-mentioned method of manufacturingcompound A the borane for the reduction in step a) is generated in situeither from the combination of NaBH₄ and I₂ or from the combination ofNaBH₄ and BF₃—OEt₂.

In another preferred embodiment of the above-mentioned method of one ofmanufacturing compound A the acid HX is selected from tosylic acid orhydrochloric acid.

In a further embodiment of the above-mentioned method of one ofmanufacturing compound A the pharmaceutically acceptable acid HY incompound B is HCl.

In another aspect the invention relates to a method of manufacturingcompound C

wherein HX is tosylic acid, hydrochloric acid or sulphuric acid,comprising the steps i), ii) and iii),wherein in step i) 4-cyano-piperidine is contacted first with an acidand is then reacted with ammonia in order to obtain intermediate E

and wherein in step ii) intermediate E is reacted with compound D in thepresence of a base

and wherein in step iii) the acid HX is added.

In a preferred embodiment of the above-mentioned method of manufacturingcompound C 4-cyano-piperidine is contacted with hydrochloric acid and isthen reacted with ammonia in order to obtain intermediate E in step i).

In a preferred embodiment of the above-mentioned method of manufacturingcompound C the intermediate E is reacted with compound D in the presenceof sodium methanolate in step ii).

In a further aspect the invention relates to intermediates of formulaVIII

and their salts.

In a further aspect the invention relates to intermediates of formula IX

-   -   and their salts,    -   wherein S* stands for a sulphur atom that represents a chiral        center.

Compounds of the general formulas I, II und III contain basic groups.Therefore compounds of the general formulas I, II und III may form saltswith pharmaceutically acceptable inorganic acids such as hydrochloricacid, sulphuric acid, phosphoric acid, sulphonic acid or with organicacids (such as for instance maleic acid, fumaric acid, citric acid,tartaric acid or acetic acid).

As described above the compounds of formulas I, II and III may betransformed into their pharmacologically acceptable salts for their useas pharmaceutics. For instance these compounds may form physiologicallyand pharmacologically acceptable acid addition salts with inorganic orwith organic acids. In order to produce these acid addition salts of thecompounds of formulas I, II and III for instance hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, methyl sulphonicacid, acetic acid, fumaric acid, succinic acid, lactic acid, citricacid, tartaric acid and maleic acid may be used. Further it is possibleto use mixtures of the aforementioned acids.

The compounds of formulas I, II and III may also be present in the formof their individual optic isomers or enantiomers, in mixtures of theindividual enantiomers or in the form of their racemates, and in theform of their free bases or in the form of their acid addition saltswith pharmacologically acceptable acids (for instance acid additionsalts with hydrohalogenic acids such as hydrochloric acid or hydrobromicacid or with organic acids such as oxalic acid, fumaric acid, diglycolicacid or methyl sulfonic acid.

The compounds of the invention may also be present in their racemicforms, but may also be present in the form of one pure enantiomers, thatmeans in their (R)- or in their (S)-forms.

As mentioned before the pharmacologically acceptable salts of thecompounds of formula I, II and III are also a preferred aspect of theinstant invention. These pharmaceutically acceptable salts of thecompounds of formulas I, II and III may also be present in the form oftheir hydrates (for instance mono- or dihydrates) and/or in the form oftheir solvates.

A solvate of a compound of formula I, II or III is defined herein as acrystalline salt of the respective compound of formula I, II or IIIwhich contains solvent molecules (for instance ethanol, methanol etc.)within its crystal lattice.

A hydrate of a compound of formula I, II or III is defined herein as acrystalline salt of a compound of formula I, II or III which containscrystalline water in its crystal lattice.

3 METHODS OF SYNTHESIS Generation of Examples 1 and 2

3.1. Generation of Compound VII

3.1.1 Synthesis of Dimethyl-3-thiaadipate (Compound III)

Methyl thioglycolate (292 g, 2.61 mol) and piperidine (4.43 g, 0.052mol) were charged to an inerted jacketed reactor equipped with anaddition funnel, mechanical stirrer, N₂ line and thermocouplethermometer. Methyl acrylate (250 g, 2.87 mol) was then added slowlyover a period of 30 min keeping the temperature at approximately 45° C.Upon complete addition, the mixture was stirred at 45° C. for 30 minPiperidine (17.9 g, 210 mmol) was added and stirring at 45° C. continuedfor 30 min (in order to scavenge of excess acrylate).Tert-butylmethylether (MTBE) (251 ml) was charged, the mixture wascooled to 15° C. and 1 M HCl (251 ml) was added. The mixture was stirredfor 5 min and the organic layer was collected and washed with water (251ml). The mixture was concentrated to a minimum volume by distillationunder reduced pressure at 50° C. Dichloromethane (251 ml) was chargedand the mixture was again concentrated under reduced pressure bydistillation at 40-45° C. Crude product III (480 g) was used in the nextstep without further purification.

3.1.2 Synthesis of Methyl-3-oxo-tetrahydrothiophene-2-carboxylate(Compound IV)

TiCl₄ (1.0 M CH₂Cl₂, 1.16 L; 1.16 mol) was charged to an inerted anddried jacketed reactor equipped with temperature probe, mechanicalstirrer and a dropping funnel. The reactor contents were cooled to −10°C. and isopropanol (89.6 ml, 1.16 mol) was charged at or below −10° C.The mixture was stirred at −10° C. for 30 min and dimethyl 3-thiaadipate(200 g, 1.01 mol) was charged slowly over 1 h keeping the internaltemperature at or below −10° C. The reaction was stirred for anadditional 30 min at −10° C. and Et₃N (489 mL, 3.49 mol) was slowlycharged over 1.5 hours keeping the internal temperature at or below −10°C. The mixture was stirred at or below −10° C. for 1.5 hours. 3 N HCl(1.01 L; 3.03 mol) was slowly charged keeping the internal temperaturebelow 10° C. The temperature was increased to 30° C. and the mixture wasstirred for 1 hour. The mixture was allowed to settle, the organic layerwas collected and the aqueous layer was extracted with dichloromethanetwice (1.5 l per extraction). The combined organic portions were washedtwice with water (1.5 l per wash) and dried with MgSO₄ (40 g). Theresulting solution was concentrated to a minimum volume under reducedpressure at 25-35° C. to afford crude IV (148.6 g). The spectral data ofIV is consistent with literature values (Liu, H.-J.; Teng, K. N. Can. J.Chem. 1982, 60, 437).

3.1.3 Synthesis of 3-Ureido-4,5-dihydro-thiophene-2-carboxylic acidmethyl ester (Compound V)

Urea (2.16 kg, 35.9 mol) was charged into a dry, jacketed reactorequipped with a stirrer, N₂ line and thermocouple thermometer.3-oxo-tetrahydro-thiophene-2-carboxylic acid methyl ester (Compound IV,3.0 kg) was charged followed by methanol (4.5 l). Conc. HCl (297 ml,3.59 mol) was charged at 20-25° C. and the mixture stirred at reflux for4-6 hours. The reaction mixture was cooled to 0° C. and the resultingsolid was collected by filtration. The cake was washed with water twice(2 l water per wash) and dried in a vacuum oven at 50° C. to afford 4.17kg (83% w/w) of compound V (95% yield), ¹H NMR (500 MHz, (CD₃)₂SO).3.10(dd, 2H, J=8.5, 8.5 Hz), 3.50 (dd, 2H, J=8.5, 8.5 Hz), 3.73 (s, 3H),6.50-7.20 (bs, 2H), 9.47 (s, 1H); ¹³C NMR (125 MHz, (CD₃)₂SO) • 28.7,37.8, 52.4, 100.0, 151.6, 154.7, 165.7; LCMS (EI) for C₇H₁₁N₂O₃S, (M+H)+calcd. 203.0, measd. 203.0.

3.1.4 Synthesis of 6,7-Dihydro-thieno[3,2-d]pyrimidine-2,4-diol(Compound VI)

Compound V (2.0 kg, 9.47 mol) was added to a solution of water (6.0 l)and NaOH (379 g, 9.47 mol) at normal room temperature. The above mixturewas stirred at 85° C. for 3 hours. After cooling to 0° C., conc. HCl(861 ml, 10.4 mol) was added slowly until the pH of the solution was0-1. The mixture was cooled to 0° C., stirred for 5-10 min and theresulting solid was collected by filtration. The cake was washedthoroughly with water twice (1 l per rinse), air-dried for 2-3 hours(suction) and then dried further in a vacuum oven at 50° C. for 12-16hours to afford 1.67 kg of compound VI. ¹H NMR (500 MHz, (CD₃)₂SO) •3.11 (dd, 2H, J=8.5, 8.5 Hz), 3.31 (dd, 2H, J=8.5, 8.5 Hz), 11.14 (s,1H), 11.38 (s, 1H); ¹³C NMR (125 MHz, (CD₃)₂SO) • 29.3, 35.4, 108.5,150.5, 152.4, 160.4; LCMS (EI) for C₆H₇N₂O₂S, (M+H)⁺ calcd. 171.0,measd. 171.0.

3.1.5 Synthesis of 2.4-dichloro-thieno[3,2-d]pyrimidine (Compound VII)

800 g of solid Compound VI (4.66 mol) was charged into to an inert anddry jacketed reactor (reactor 1) equipped with a temperature probe,mechanical stirrer and a dropping funnel. 1.5 liter (9.31 mol)Diethylaniline was charged over 30 min to 1 h keeping the temperature ator below 25° C. The internal temperature was brought up to 105-110° C.and 0.68 equiv. (868 ml, 34% of the total) of phosphorus oxychloride wasadded into the reactor (reactor 1) over 5-10 min. When the insidetemperature began to decrease, the internal temperature was maintainedat 110° C. and addition of the remaining POCl₃ (1.32 equiv. or 66% ofthe total) resumed over a period of 30-40 min. The internal temperaturewas adjusted to 105-110° C. and the mixture was stirred for 18-24 h oruntil complete (HPLC analysis). The mixture was cooled to 45° C. and THF(400 mL) was charged at 45° C. The above crude mixture was placed into asecondary dry vessel or reactor (vessel or reactor 2). 4.8 l of waterwas charged into the reactor 1 and cooled to 5° C. The crude reactionmixture (in reactor or vessel 2) is then slowly charged into reactor 1containing water keeping the temperature at 5-10° C. The mixture wasstirred at 5° C. for 30 min to 1 h and the resulting solid was collectedby filtration. The cake was rinsed with water twice (1.6 l per rinse)and the cake was air dried in the funnel for 6-8 h to afford 964 g (92%w/w; 88% yield) of crude Compound VII. Dichloromethane (4.6 L) ischarged into a 10 L reactor. Crude Compound VII and activated carbon(46.2 g) were charged into the reactor, the mixture is heated to 40° C.and stirred for 20 min. The resulting solution was collected byfiltration through a filter media to remove charcoal. The cake wasrinsed with dichloromethane twice (175 ml per rinse). The solution wasconcentrated under reduced pressure to a minimum stirrable volume andthe remaining dichloromethane was chased away by distillation with aminimum amount of petroleum ether. Additional petroleum ether (1.3 l)was charged into the reactor, the mixture was cooled to 10° C. andstirred for 1 hr. The resulting solid was collected by filtration andthe cake was rinsed with petroleum ether twice (150 ml per rinse). Thecake was air dried in the funnel (suction) until it appeared dry. Theresulting solid Compound VII was transferred to a suitable taredcontainer and dried in an oven at 50° C. for 6 hr to get final product:¹H NMR (400 MHz, DMSO-d6) • 3.45-3.56 (m, 4H); ¹³C NMR (400 MHz,DMSO-d6) • 29.3, 36.5, 134.8, 151.0, 154.1, 175.9.

3.2 Generation of Example 1

3.2.1 Synthesis of Compound A

NaBH₄ (28.6 g, 757 mmol, 2.87 eq) and THF (500 ml) were charged to a 2 Lreactor under nitrogen and the mixture was cooled to −5° C. A solutionof I₂ (63.6 g, 251 mmol, 0.95 eq) in 125 mL THF was prepared and addedto the reactor slowly over 45 min maintaining an internal temp of −5 to5° C. The addition funnel was then rinsed with 42 mL THF. Compound B (50g, 264 mmol, 1 eq) was then charged at −6° C., then the temperature roseto approx. 5° C. The reaction mixture was then heated to 65° C. for 23 h(Note: Reaction conversion was analyzed by GC/FID by quenching 0.1 mLreaction mixture with MeOH, then derivatizing with 0.5 mL of a 5/2/2mixture of THF/acetic anhydride/TEA). 83 mL MeOH were then charged tothe reaction mixture slowly over 20 min maintaining the temperaturebetween 20-27° C. The reaction mixture was concentrated to a minimumstirrable volume and 500 mL 2-methyltetrahydrofurane (MeTHF) were added.485 g of 25 wt % aq. NaOH (11.5 eq) were then added, solids weredissolved. The layers were separated and the aqueous phase was extractedtwice with 500 ml 2-methyltetrahydrofurane (MeTHF). The organics werethen filtered through a pad of celite and MgSO₄ and rinsed with 50 mL2-methyltetrahydrofurane (MeTHF). A solution of p-toluenesulfonic acidmonohydrate (51 g, 264 mmol, 1 eq) in MeTHF (100 ml) was prepared andadded to the organics (alternatively HCl may be used to obtain theHCl-salt of compound A). A homogeneous light yellow solution resulted.The solution was concentrated to ˜275-300 mL and the water content waschecked. Additional MeTHF was added and concentrated to the originalvolume until the water content was <0.1%. The resulting solid wasfiltered and rinsed with 50 ml MeTHF, left to dry in the funnelovernight and then dried further in the vacuum oven at 50° C. 61.71 g ofcompound A were collected:

¹H NMR (DMSO-d6, 400 MHz) • 1.70-1.92 (m, 2H), 1.94-2.03 (m, 2H),2.04-2.18 (m, 2H), 2.29 (s, 3H), 3.55 (s, 3H), 5.47 (br s, 1H), 7.13 (d,J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.95 (br s, 3H); ¹³C NMR(DMSO-d6, 100 MHz) • 13.3, 20.8, 56.4, 63.5, 125.5, 128.1, 137.8, 145.4

3.2.2 Synthesis of Compound VIII

Intermediates VII (180 g, 852 mmol) and A (129 g, 937 mol) weresequentially charged into a multi-neck vessel equipped with a condenser,thermocouple thermometer and nitrogen line. Acetonitrile (900 ml) andtriethylamine (594 ml, 4.26 mol) were then added at 22° C. and themixture was stirred at 75-77° C. for 12 h. Water (1.2 l) was chargedslowly over 20 min, the mixture was seeded with Compound VIII crystals(0.3 g) at 40° C. and then cooled to 25° C. over 2 h. The mixture wasstirred for an additional 12 h at normal room temperature and theresulting solid was collected by filtration. The filter cake was rinsedwith 2:1 mixture of water/MeCN (400 mL) followed by water (200 ml). Theresulting solid was dried under vacuum at 50° C. for 12 h to afford 132g (57% yield) of compound VIII: ¹H NMR (400 MHz, CDCl₃) • 1.85-2.05 (m,2H), 2.10-2.21 (m, 2H), 2.32-2.41 (m, 2H), 3.27 (dd, J=8.0, 8.4 Hz, 2H),3.43 (dd, J=8.0, 8.4 Hz, 2H), 3.91 (s, 2H), 4.67 (s, 1H); ¹³C NMR(CDCl₃, 100 MHz).14.8, 30.7, 31.2, 36.7, 59.7, 67.6, 114.7, 156.1,156.2, 168.0.

3.2.3 Synthesis of Compound IX

Compound VIII (122 g, 429 mmol), S-(−)-1,1′-Bi-2-naphthol (S-(−)-BINOL)(12.4 g, 42.9 mmol), dichloromethane (608 mL), Ti(OiPr)₄ (6.54 mL, 21.4mmol), and water (7.72 ml, 429 mmol) were charged to a 2 l multi-neckflask at 20° C. under nitrogen and stirred for 1 h. tert-Butylhydroperoxide (70% in water, 62.3 ml, 472 mmol) was added at once at 21°C.; the mixture became completely homogeneous and the temperature roseto approx. 40° C. The mixture was allowed to reach normal roomtemperature, was stirred for 1.5 h and filtered. The cake was twicerinsed with isopropyl acetate (243 ml per rinse) and the cake wasair-dried in the filter for >6 h to afford 114.4 g of compound IX.

¹H NMR (400 MHz, DMSO-d6) • 1.70-1.85 (m, 2H), 2.14-2.34 (m, 4H),2.98-3.08 (m, 1H), 3.09-3.19 (m, 1H), 3.30-3.40 (obscured m, 1H),3.50-3.62 (m, 1H), 3.65-3.77 (m, 2H), 4.91 (t, J=6 Hz, 1H), 8.63 (s,1H); ¹³C NMR (100 MHz, DMSO-d6) • 14.5, 29.6, 29.8, 32.6, 48.6, 59.2,62.8, 119.0, 157.8, 161.4, 175.3.

The other enantiomer of compound IX may be produced whenS-(−)-1,1′-Bi-2-naphthol is replaced by R-(+)-1,1′-Bi-2-naphthol. Aracemate of compound IX may be produced methods known by those skilledin the art that exclude chiral agents and conditions. An example forsuch a procedure to produce racemic sulfoxides is given in WO 06/111549.

3.2.4 Synthesis of Example 1

Sulfoxide IX (6.48 g; 22.5 mmol), 4-(4-Chlorophenyl)-piperidinehydrochloride C (5.75 g; 24.8 mmol) (alternatively the p-TsOH-salt orthe H₂SO₄-salt of compound C) and N,N-diisopropylethylamine (12.4 ml;72.1 mmol) were mixed in 47 ml of dioxane. The resulting mixture wascharged to three 20 ml vials which were heated to 120° C. for 25 min ina microwave oven. After cooling to room temperature, the reactionmixtures were poured on ice water. The resulting precipitate wasfiltered off, taken up in 500 ml ethyl acetate and heated to reflux.After refluxing, the mixture was cooled in an ice bath and the resultingprecipitate was filtered off and dried in a dry box at 50° C. at reducedpressure yielding 7.57 g of Example 1.

¹H NMR (400 MHz, DMSO-d6) • 1.43-1.57 (m, 2H), 1.67-1.85 (m, 4H),2.11-2.21 (m, 2H), 2.26-2.43 (m, 2H), 2.80-3.01 (m, 5H), 3.17-3.47 (m,integration compromised by water peak), 3.67-3.76 (m, 2H), 4.74-4.86 (m,3H), 7.25-7.36 (m, 5H).

¹³C NMR (100 MHz, DMSO-d6) • 14.3, 29.4, 29.6, 32.3, 32.5, 41.4, 44.2,48.5, 58.4, 63.6, 109.2, 128.2, 128.6, 130.5, 144.7, 157.6, 161.5, 174.7

3.3 Generation of Example 2

3.3.1 Generation of Compound G

3.3.1.1 Synthesis of Compound E

4M HCl in dioxane (225 ml, 3 eq, 900 mmol) was charged to a 500 ml3-neck jacketed reactor equipped with a mechanical stirrer, temperatureprobe and argon line. The solution was cooled to 0° C. and4-cyanopiperidine (33.04 g, 300 mmol) was charged followed by methanol(36.4 ml, 900 mmol, 3 equiv) over ˜30 min while keeping the temperaturebelow 10° C. (temperature rose). The above mixture was stirred for 6-8 hat normal room temperature until complete conversion was observed by ¹HNMR analysis of an aliquot in D₂O (the clear solution turned into awhite slurry after 30 min) The mixture was cooled to 5° C. and 25 wt %NaOMe in methanol (129.6 g, 600 mmol, 2 eq) was charged whilemaintaining the temperature below 15° C. The mixture was then stirredfor 1 h. 7.0 N ammonia in methanol (64.2 ml, 1.5 eq, 450 mmol) wascharged to the above mixture and stirred for 2 h at normal roomtemperature. The mixture was concentrated under reduced pressure at 60°C. to a volume of ˜250 ml to afford a solution of crude compound E thatwas used without isolation:

¹H NMR (400 MHz, D₂O) • 1.80-1.95 (m, 2H), 2.15 (br d, J=4.4 Hz, 2H),2.79-2.90 (m, 1H), 3.02 (ddd, J=13.2, 13.2, 3.0 Hz, 2H), 3.48 (m, 2H).

3.3.1.2 Synthesis of Compound G

The above solution of intermediate compound E was cooled to ˜20° C. and25 wt % NaOMe in methanol (162 g, 2.5 eq, 750 mmol) was charged. Themixture was then stirred for 30 min Compound D(=(Z)—N-(2-chloro-3-(dimethylamino)allylidene)-N-methylmethan-aminiumhexafluorophosphate (V)), (82.3 g of 95 wt % purity, 0.85 eq, 255 mmol)was charged to the above mixture in two portions at normal roomtemperature over ˜30 min and stirred for 3 h at room temperature. Themixture was concentrated under reduced pressure at 60° C. to a volume of˜200 ml. 2-Methyltetrahydrofuran (400 ml) was charged and the mixturewas concentrated further to a volume of ˜150 ml under reduced pressureat 60° C. 2-methyltetrahydrofuran (250 ml) was charged, the mixture wascooled to ˜20° C., water (150 ml) was added and the mixture was stirredfor 5 min. The layers were separated and the organic layer wascollected. The organic layer was washed with 30% aqueous NaOH (120 ml)and the layers were separated. The organics were concentrated to aminimum stirrable volume (˜150 mL) and n-propanol (350 ml) was charged.A solution of p-toluenesulfonic acid monohydrate in n-propanol (0.85equiv., 255 mmol, 48.4 g in 100 ml n-propanol) was charged to the aboveclear solution over 10 min at ˜65° C. The above mixture was concentratedat ˜65° C. under reduced pressure to maintain ˜350 ml and <1.0% water(it is recommended to have a water content below 1.0% to avoid productlosses to the mother liquor). The batch was cooled to 20° C. withstirring over 3 h. The solids were filtered, rinsed with the filtrateand then with n-propanol (120 mL) to afford 111 g (68% w/w by assay,75.48 g) of compound G after vacuum drying at 65° C. in a vacuum ovenfor 12 h.

¹H NMR (DMSO-d6, 400 MHz) • 1.83-1.99 (m, 2H), 2.13 (d, J=12 Hz, 2H),2.97 (s, 3H), 3.0-3.11 (m, 2H), 3.13-3.23 (m, 1H), 3.30-3.42 (m, 2H),7.14 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.0 Hz, 2H), 8.47 (br, 2H), 8.91 (s,2H); ¹³C NMR (DMSO-d6, 100 MHz) • 20.7, 27.0, 40.8, 42.8, 125.5, 128.1,128.8, 137.9, 145.2, 155.8, 169.0.

3.3.2 Synthesis of Example 2

Compound IX (86.5 g, 291 mmol, 1 eq), compound G (160 g, 305 mmol, 1.05eq), tetrahydrofuran (THF) (484 ml), water (121 ml) and DIPEA(N,N-diisopropylethylamine, 127 ml, 727 mmol, 2.5 eq) were all chargedto a 3 l round bottom flask under nitrogen and heated to 65° C. for 3 h.Water (1125 ml, 13 ml/g compound IX) was then charged at the temperature65° C. and stirred for 2 h while cooling to 20° C. The mixture wasfiltered and the cake was washed twice with 173 ml acetone. The cake wasthen left to dry on the funnel overnight to afford 116.7 g of Example 2:

¹H NMR (400 MHz, CDCl₃) • 1.75-1.95 (m, 4H), 2.02-2.11 (m, 2H),2.12-2.26 (m, 2H), 2.38 (q, J=9.6 Hz, 2H), 2.93-3.12 (m, 4H), 3.12-3.22(m, 1H), 3.28-3.39 (m, 1H), 3.53-3.65 (m, 1H), 3.80 (d, J=5.6 Hz, 2H),4.42 (t, J=5.2 Hz, 1H), 4.82 (br d, J=11.2 Hz, 2H), 6.47 (s, 1H), 8.62(s, 2H); ¹³C NMR (100 MHz, CDCl₃) • 14.8, 30.0, 30.1, 30.6, 32.7, 44.3,49.4, 59.1, 68.2, 107.5, 129.1, 155.5, 159.0, 162.3, 170.5, 174.6.

3.3.2.1 Crystallization to Anhydrous Form A of Example 2

Preparation of Seed Crystals (Anhydrous Form A)

Small amounts of crude Example 2 (1-2 mg) were suspended inapproximately 0.1 ml of the following solvents: ethanol, acetone,2-butanone, ethyl acetate, isopropyl acetate, tetrahydrofuran,1-propanol, 2-butanol, and acetonitrile. After a heating/cooling cycle,the samples resulted in suspensions of crystalline anhydrous Form A asanalysed by X-ray powder diffraction.

a. Crystallization from Acetic Acid, Dimethyl Sulfoxide, orN-Methyl-2-Pyrrolidone:

Approximately 1 g of crude Example 2 is dissolved in 10 ml of a polarorganic solvent such as acetic acid, dimethyl sulfoxide, orN-methyl-2-pyrrolidone at a temperature of >60° C. The solution iscooled to 30-40° C. and an antisolvent (approximately 5-10 ml) such asisopropyl alcohol, ethyl alcohol, or acetone is added. The solution isseeded with anhydrous Form A crystals of Example 2 and cooled to 20° C.An additional amount of antisolvent (5-10 ml) is added to increase theyield. The resulting slurry is filtered within 1 hr of cooling and thewet cake is dried at 60° C. under vacuum. Anhydrous Form A is obtainedas a white solid as confirmed by X-ray powder diffraction (XRPD) of theanhydrous Form A standard on file.

b. Crystallization from Tetrahydrofuran/Water:

Approximately 1 g of crude Example 2 is dissolved in 10 ml oftetrahydrofuran/water mixture (8:2, v/v) at a temperature of >60° C. Thesolution is cooled to 40-50° C., seeded with anhydrous Form A crystalsof Example 2, and further cooled to 20° C. in less than 1 hr.Approximately 5-10 ml of antisolvent (an organic solvent such asisopropyl alcohol, ethyl alcohol, or acetone) is added to the slurry.The resulting slurry is filtered within 1 hr after the antisolventaddition and the wet cake is dried at 60° C. under vacuum. AnhydrousForm A is obtained as a white solid as confirmed by X-ray powderdiffraction (XRPD) of the anhydrous Form A standard on file.

c. Drying from Dihydrate:

Approximately 1 g of the Dihydrate form of Example 2 is washed withapproximately 5 ml of an anhydrous solvent such as ethanol, methanol,isopropanol, or acetone on a buchner funnel. The wet cake is then driedat 60° C. under vacuum. Anhydrous Form A is obtained as a white solid asconfirmed by X-ray powder diffraction (XRPD) of the anhydrous Form Astandard on file.

3.3.2.2 Crystallization to Anhydrous Form B of Example 2

Preparation of Seed Crystals of Anhydrous Form B

Small amounts of crude Example 2 (1-2 mg) were suspended inapproximately 0.1 ml of 2-propanol and water mixtures (one with 3.3% ofwater and another with 6.6% water). After a heating/cooling cycle, thesamples resulted in suspensions of crystalline anhydrous Form B by X-raypowder diffraction analysis. The samples in anhydrous 2-propanolsubjected to the same conditions resulted in the mixture of Form A andForm B as analysed by X-ray powder diffraction. The mixture of Form Aand Form B, slurried at 20° C. for 4 days in mixtures of water and thefollowing solvents: methanol, ethanol, 2-propanol, 1-propanol, andacetone (all with approximately 9% water), resulted in Form B asanalysed by X-ray powder diffraction.

a. Crystallization from n-Propanol/Water:

10 g of crude Example 2 is dissolved in 160 ml of n-propanol/watermixture (9:1, v/v) at a temperature of >65° C. The solution is cooled to60° C., seeded with anhydrous Form B crystals of Example 2, and aged for0.5 hr. The slurry is cooled to 30° C. over at least 5 hrs. Optionallythe slurry is distilled at 30° C. under reduced pressure to reduce thevolume to approximately 80-100 ml in order to maximize the yield. Theslurry is further cooled to 0° C. and the slurry is aged for at least 8hrs or until anhydrous Form A is no longer detected. The slurry isfiltered and the wet cake is dried at 60° C. under vacuum. AnhydrousForm B of Example 2 is obtained as a white solid in a 90% yield. X-raypowder diffraction (XRPD) conforms to the anhydrous Form B standard onfile.

b. Crystallization from Tetrahydrofuran/Water:

Approximately 1 g of crude Example 2 is dissolved in 10 ml oftetrahydrofuran/water mixture (8:2, v/v) at a temperature of >60° C. Thesolution is cooled to 40-50° C., seeded with anhydrous Form B crystalsof Example 2, and is further cooled to 20° C. over 2 hrs. Approximately10 ml of antisolvent (an organic solvent such as isopropyl alcohol,ethyl alcohol, or acetone) is added to the slurry. The resulting slurryis aged for at least 8 hrs or until anhydrous Form A is no longerdetected. The slurry is then filtered and the wet cake is dried at 60°C. under vacuum. Anhydrous Form B of Example 2 is obtained as a whitesolid. X-ray powder diffraction (XRPD) conforms to the anhydrous Form Bstandard on file.

c. Conversion from Dihydrate:

Approximately 1 g of Dihydrate of Example 2 is suspended in 5-10 ml ofan anhydrous solvent such as ethanol, methanol, isopropanol, acetone,ethyl acetate, isopropyl acetate, tetrahydrofuran, or acetonitrile. Thesuspension is seeded with anhydrous Form B crystals of Example 2 andstirred at 20-40° C. for at least 4 hrs or until the conversion toanhydrous Form B is complete as checked by X-ray powder diffraction(XRPD) analysis.

d. Conversion from Anhydrous Form A:

Approximately 1 g of anhydrous Form A of Example 2 is suspended in 5-10ml of an anhydrous solvent such as ethanol, methanol, isopropanol,acetone, ethyl acetate, isopropyl acetate, tetrahydrofuran, oracetonitrile. The suspension is seeded with anhydrous Form B crystals ofExample 2 and stirred at 20-40° C. for at least 4 hrs or until theconversion to anhydrous Form B is complete as checked by X-ray powderdiffraction (XRPD) analysis.

3.3.2.3 Crystallization to Dihydrate Form of Example 2

Preparation of Seed Crystals of the Dihydrate Form

The mixture of anhydrous Form A and anhydrous Form B crystals of Example2, slurried at 20° C. for 4 days in 2-butanone/water (with 9% water),resulted in the Dihydrate crystals as confirmed by X-ray powderdiffraction analysis.

a. Crystallization from n-Propanol/Water:

10 g of crude Example 2 is dissolved in 120 ml of n-propanol/watermixture (8:2, v/v) at a temperature of >65° C. The solution is cooled to50° C., seeded with Dihydrate crystals of Example 2, and aged for 0.5hr. Water (approximately 60-100 ml) is added to the slurry. The slurryis cooled to 20° C. over at least 5 hrs and then aged for at least 8hrs. The slurry is filtered, and the wet cake is washed with water andthen air-dried.

b. Crystallization in THF/Water:

Approximately 1 g of crude Example 2 is dissolved in 10 ml oftetrahydrofuran/water mixture (8:2, v/v) at a temperature of >60° C. Thesolution is cooled to 30-50° C., seeded with Dihydrate crystals ofExample 2, and further cooled to 20° C. over 2 hrs. Approximately 10 mlof water is added to the slurry. The resulting slurry is aged for atleast 8 hrs. The slurry is filtered, and the wet cake is washed withwater and then air-dried. X-ray powder diffraction (XRPD) of the productshows the Dihydrate pattern.

c. Conversion from Anhydrous Form A or from Anhydrous Form B:

Approximately 1 g of anhydrous Form A or of anhydrous Form B of Example2 is suspended in approximately 5-10 ml of a mixture of at least 30%water and an organic solvent such as ethanol, methanol, isopropanol,acetone, or tetrahydrofuran. The suspension is seeded with Dihydratecrystals of Example 2 and stirred at 20° C. for at least 4 hrs or untilthe conversion to the Dihydrate Form is complete as checked by X-raypowder diffraction (XRPD) analysis. The slurry is filtered, and the wetcake is washed with water and then air-dried.

The polymorphs of Example 2 were characterized by X-ray powderdiffraction (XRPD) as shown in FIGS. 3 a, 3 b and 3 c showing the X-raypowder diffraction diagrams and the tables with all observable reflexpeaks. For the performance of the X-ray powder diffraction analysis aRigaku Miniflex II instrument was used with an X-ray generator of thetype Power 450 W (30 kV-15 mA) (Optics: variable divergence slit). TheGoniometer range was 3.0-35.0°2 • and the scan speed was 0.02° 2•/minwith an accuracy of more than 0.01°. As a monochromator a foilfilter/graphite was used and as a detector the scintillation counter Nal23.0 mm diameter was used. The sample was analysed on a low backgroundSi (510) sample holder.

The polymorphs of Example 2 were further characterized by differentialscanning calorimetry (DSC) with a TA Instruments DSC Q1000 as shown inFIGS. 4 a, 5 a and 6 a. The samples were analyzed in an unsealedAluminium pan under an N₂ flow. The ramp that was used for themeasurements was 10° C./min from 20° C. to 300° C.

The polymorphs of Example 2 were further characterized bythermogravimetric analysis (TGA) with a TA Instruments TGA Q500 as shownin FIGS. 4 b, 5 b and 6 b. The samples were analyzed in an open platinumsample pan under N₂ flow. The ramp that was used for the measurementswas 10° C./min from 20° C. to 300° C.

FIGURES

FIG. 1 a: gastric emptying for rats that had received Example 1

FIG. 1 b: intestinal transit for rats that had received Example 1

FIG. 2 a: gastric emptying for rats that had received Example 2

FIG. 2 b: intestinal transit for rats that had received Example 2

FIG. 3 a: X-ray powder diffraction diagram of anhydrous form A ofExample 2

FIG. 3 b: X-ray powder diffraction diagram of anhydrous form B ofExample 2

FIG. 3 c: X-ray powder diffraction diagram of dihydrate form C ofExample 2

FIG. 4 a: Differential Scanning calorimetrie (DSC) of the anhydrous FormA of Example 2 (DSC indicates a melt endotherm at about 235° C.,followed by a decomposition when heating continued above melting)

FIG. 4 b: Thermogravimetric Analysis (TGA) of the anhydrous Form A ofExample 2 (TGA indicates non-solvated form as shown by negligiblevolatile content (minimal weight loss of (0.145%) up to the meltingtemperature)

FIG. 5 a: Differential Scanning calorimetrie (DSC) of the anhydrous FormB of Example 2 (DSC indicates either a solid-solid transition or asimultaneous melt/recrystallization occurring at about 218° C. Theresulting form is most likely anhydrous form A as indicated by the meltexotherm at 235° C., corresponding to the melting point of form A. Afterthe melting of form A the compound is decomposed when heated above 240°C.)

FIG. 5 b: Thermogravimetric Analysis (TGA) of the anhydrous form B ofExample 2 (TGA shows negligible volatile content for form B (indicatednon-solvated form) as shown by the minimal weight loss (0.057%) up tothe melting temperature)

FIG. 6 a: Differential Scanning calorimetrie (DSC) of the dihydrate FormC of Example 2 (DSC indicates low temperature dehydration as indicatedby the broad endotherm at <100° C. The dehydrated solid is most likelyform A as indicated by the melt endotherm occurring at about 236° C.characteristic of form A. Form A is then decomposed when heated abovemelting temperature),

FIG. 6 b: Thermogravimetric Analysis (TGA) of the dihydrate form C ofExample 2 (TGA shows a large weight loss for form C indicating thedehydration by heating at <100° C. The dehydrated material (likely formA) shows almost no weight loss up to melting (from 100° C. to 236° C.)consistent with the previous observations for form A)

4 EXAMPLES

The following Examples were prepared analogously to the methods ofsynthesis described hereinbefore.

TABLE A Chemical structures of the example compounds of the instantinvention Example No. Chemical Structure 1

2

The following Prior Art compounds A to D are the structurally closestcompounds disclosed in WO 2009/050248 which is the closest piece ofprior art.

TABLE B: Chemical structures of the structurally closest compoundsdisclosed in WO 2009/050248. Prior art compound Chemical Structure Priorart compound A (= Example 2 of WO 2009/ 050248)

Prior art compound B (= Example 27 of WO 2009/ 050248)

Prior art compound C (= Example 34 of WO 2009/ 050248)

Prior art compound D (= Example 39 of WO 2009/ 050248)

5 BIOLOGICAL EXPERIMENTS 5.1 Determination of the PDE4B IC₅₀-Values (InVitro)

The IC₅₀-values of the compounds of the invention (Example Compounds 1and 2) and of the above-mentioned prior art compounds A to D withrespect to their PDE4B-inhibiting ability have been determined with aScintillation Proximity (SPA) Assay (GE Healthcare, No. TRKQ7090).

The Scintillation Proximity (SPA) Assay is based on the detection of thedifferent affinities of the cyclic 3″-5″-adenosine monophosphate (cAMP,low affinity) and the linear 5′-adenosine monophosphate (AMP, highaffinity) to yttrium-silicate-scintilator beads. The cAMP-specificphosphodiesterase (PDE) PDE4B cleaves the 3′-phosphodiester bond of thetritium-labelled-[³H]cAMP to the [³H]5′-AMP. This [³H]5′-AMP associateswith the scintillator beads because of their higher affinity and causesscintillations (light flashes) which can be measured in a WallacMicrobeta Scintillation Counter.

10 μl of a [³H]cAMP-solution (0.05 μCi in H₂O, 10-30 Ci/mmol) are addedto 89 μl of a PDE4B-enzyme-solution (active site fragment comprising theamino acids 152-484; 0.15-0.18 ng) in assay buffer (50 mM Tris HCl pH7.5; 8.3 mM MgCl₂; 1.7 mM ethylene glyclol tetraacetic acid (EGTA); 0.25mg/ml bovine serum albumin (BSA)) and this mixture is incubated at 30°C. for one hour

a) without the compound to be tested (in the presence of 1 μldimethylsulfoxide (DMSO), corresponding to 1% DMSO) and

b) in the presence of the compound to be tested in a concentration of125 μM, 25 μM, 5 μM, 1 μM, 200 nM, 40 nM, 8 nM, 1.6 nM, 0.32 nM, 0.064nM, 0.0128 nM (dilution series in 5er-steps beginning from 125 μM until0.0128 nM, in the presence of 1% DMSO).

After this incubation the reaction is stopped by the addition of 50 μlof bead-solution (500 mg beads/35 ml H₂O, 18 mM zinc sulfate). In thefollowing 45 minutes the beads have the opportunity to form a sediment.After that the scintillations are measured in the scintillation counter.If the tested compound is able to inhibit the enzymatic activity of thePDE4B-enzyme, less [³H]AMP depending on the concentration of the testedcompound is produced and less scintillations are measurable. Theseresults are expressed as IC₅₀-values. The IC₅₀-value stands for thecompound concentration at which the PDE4B enzyme activity is inhibitedto a half maximal value. Therefore the lower the IC₅₀-value is thebetter is the PDE4B inhibition.

TABLE C Experimentally determined IC₅₀-values with respect to PDE4Binhibition for the compounds of the invention and for the Prior artcompounds as disclosed in WO 2009/050248 Experimentally determinedIC₅₀-value for Compound PDE4B inhibition [nM] Example 1 4.3 Example 27.2 Prior art compound A 3.3 Prior art compound B 66 Prior art compoundC 44 Prior art compound D 7.3

Only prior art compounds A and D have IC₅₀ values in the same potencyrange as Examples 1 and 2. Consequently all further experiments havebeen performed just with Examples 1 and 2 and with prior art compounds Aand D.

5.2 Determination of the Dose Response Relationship and Calculation ofthe Half-Maximal Effective Dose in Regard to the Inhibition ofLPS-Induced Neutrophil Influx into Bronchoalveolar Lavage Fluid of MaleWistar Rats

The anti-inflammatory activity of Examples 1 and 2 and of Prior artcompounds A and D was assessed in an in vivo LPS-induced lunginflammation model in rats.

As a measure of the pharmacological potency of the above mentionedcompounds the half-maximal effective dose (ED₅₀) in regard to theinhibition of lipopolysaccharide-induced (LPS-induced) neutrophil influxinto the bronchoalveolar lavage fluid (BALF) was determined by assessingthe dose response relationship. Bacterial endotoxins(lipopolysaccharides [LPS]) are components of the outer bacterial cellmembrane which play an important role in the pathogenesis of infectionswith gram-negative bacteria. It is known that inhalation of suchaerosolized LPS induces a dose-dependent increase in neutrophils to lungtissues and airspaces in rats which may be detected by analyzing theamount of neutrophils in the bronchoalveolar lavage fluid (BALF).However, this dose-dependent increase of neutrophils in the BALF shouldbe diminished in a dose-dependent way in the presence of an effectivePDE4-inhibitor.

Male Wistar rats (HanWistar) from an approved local distributor wereused for the experiments. The ordered weight of the animals was in therange of 200-250 g. Animals were fasted overnight before the experiment.A total number of 32 animals were used for each experiment. Eightanimals (n=8) per dose were used for the treatment groups, two animalswere used for the LPS-control (positive control) and two animals for thenegative control.

The animals of the LPS-control and of the negative control groupsreceived“vehicle only” (“vehicle only” corresponds to 10 ml/kg bodyweight 0.5% Natrosol solution). The other groups were treated with thedifferent doses of either Example compound 1, Example compound 2, Priorart compound A or Prior art compound D respectively (see Table D).

The amount of compound for the highest concentration tested for eachcompound was suspended in 10 ml 0.5% Natrosol (Hydroxyethylcellulose)solution and then diluted to the respective concentrations as shown inTable D. The respective compound suspension or “vehicle only” (10 ml/kgbody weight 0.5% Natrosol solution) was administered orally by gavage.The resulting doses of the individual compounds corresponded to Table D:

TABLE D Tested compounds and their respective doses Example 1 0.3 1.03.0 0.3 Example 2 0.01 0.10 1.00 0.1 Prior art 0.3 1.0 3.0 0.3 compoundA Prior art 0.3 1.0 3.0 0.3 compound D

The above doses were determined due to previous tests in the LPS TNF Exvivo mouse model.

One hour (0.5 hour for Prior art compound A and for Prior art compoundD) after compound application (time set to allow for sufficient exposureas guided by prior pharmacokinetic experiments) the animals were exposedto nebulised/aerosolized LPS. The whole body exposure of 12 animals eachwas performed in a plexi glas chamber. Animals wereseparated/individualized with perforated metal plates. The aerosol wasgenerated with a commercially available nebuliser (PARI Master+PARI LLnebuliser (Pari GmbH). The concentration of the nebulized LPS-solutionwas 1 mg/ml air. The duration of the LPS exposure was 30 minutes.

4 hours after the end of LPS exposure animals were anesthetised withIsoflorane and euthanised thereafter by cervical dislocation. Thetrachea was cannulated and BALF was performed using 2×5 mL lavage buffer(phosphate buffered saline (PBS)+2% BSA).

Determination of neutrophil content of the BALF was performed using anADVIA 120 blood hemacytometer (Bayer Diagnostics). Neutrophil data werenormalised (Positive Control (=LPS treatment alone)=100%, NegativeControl (no LPS treatment, administration of “vehicle only”)=0%) andexpressed as percent of LPS control. The ED₅₀ was calculated using anonlinear fit (with the Graph Pad Prism software and a sigmoidal doseresponse fit).

The ED₅₀-value is the half-maximal effective dosis of the compound inquestion with respect to its inhibition of an LPS-induced neutrophilinflux into BALF. Consequently a very small ED₅₀-value stands for a goodcapability of the respective compound to prevent neutrophil influx intothe lung tissue after LPS exposure and therefore for a good capacity ofthe respective compound to prevent inflammation of the lung tissue.Since the ED₅₀-value is unlike the IC₅₀ value not the result of an invitro assay, but the result of an in vivo assay performed in rats andsince here not only the direct inhibition of the PDE4B enzyme, but theneutrophil influx into the lung tissue after LPS-exposure is measured,the ED50 value is already a very sensitive parameter for a compound'ssuitability to serve as a therapeutic agent in inflammatory airwaydiseases like COPD and asthma (which are both inflammatory diseases).

Exposure of rats with LPS led to a distinct neutrophil influx into theBALF.

Pretreatment of rats with compounds Example 1, Example 2, Prior artcompound A and Prior art compound D led to an inhibition of theLPS-induced neutrophil influx into the BALF. The calculated ED₅₀ valuesfor the various compounds are given in Table E.

TABLE E ED₅₀ values of the tested compounds which were calculated fromthe experimental data: Example 1 0.31 Example 2 0.1 Prior art compound A1.13 Prior art compound D 6.66

The experimentally determined ED₅₀-values for the compounds of theinvention—that means for Example 1 (ED₅₀=0.31 mg/kg body weight) and forExample 2 (ED₅₀=0.1 mg/kg body weight)—demonstrate that these compoundsof the invention, Example 1 and Example 2, are between 3 to 66 timesmore potent in this assay than prior art compounds A and D.

Therefore the compounds of the invention show a better potency toprevent the influx of neutrophils into the lung tissue and are thereforea lot more suitable to be used as a therapeutic to treat inflammatoryrespiratory diseases such as asthma and COPD.

5.3 Gastric Emptying and Gastrointestinal Transit in Conscious Rats

In order to identify an active agent which is suitable to serve as atherapeutic PDE4 inhibitor it is necessary to determine whether thecompound in question is effective at a dose that does not causesignificant gastrointestinal side effects.

Gastrointestinal side effects are known to be prominent within the fieldof PDE4 inhibitors (see Diamant, Z., Spina, D.; “PDE4-inhibitors: anovel targeted therapy for obstructive airways disease”, Pulm.Pharmacol. Ther. 2011, 24 (4), pp. 353-360 and Press, N.J.; Banner, K.H.; “PDE4 Inhibitors—A Review of the Current Field”; Progress inMedicinal Chemistry 2009, 47; pp. 37-74).

The experiments 1.1 and 1.2 above have shown that the compounds of theinvention are clearly more potent with respect to PDE4B enzymeinhibition and/or more potent with respect to preventing neutrophilinflux into the lung tissue and are therefore advantageous over thestructurally related compounds disclosed in WO 2009/050248, inparticular in comparison to Compounds A, B, C and D.

In order to evaluate whether the compounds of the present invention leadto gastrointestinal side effects the compounds of the invention havebeen administered to rats 30 minutes before the rats were fed with atest meal comprising barium sulfate. After that it was tested whethergastric emptying and/or gastrointestinal transit in these rats wasaffected by the presence of these compounds.

The effects of the compounds Example 1 and Example 2 on gastric emptyingand gastrointestinal transit in conscious rats has been investigated asdescribed below. Wistar rats of both sexes weighing 130-160 g (ages:male 7 wk, female 8 wk) were used. The animals are obtained from anapproved local distributor, a minimum of four days quarantine isrequired before use, during which time the animals are maintained underroutine animal care procedures. Groups of up to 5 animals are housed incages in a room with controlled temperature and humidity and alight/dark cycle with the lights on from 6 a.m. to 6 p.m. The animalshave access to normal rodent chow and water ad libitum. The animals aretransported to the laboratory on the day of experimentation. Gastricemptying as well as small intestinal propulsion are determined using abarium sulfate test meal. Five rats Crl:WI(Han) of each sex (n=10) wereused. The animals were deprived of food 17 h prior to the experiment butallowed free access to water.

The drug under investigation (drug was suspended to the concentration of10 ml/kg body weight in 0.5% Natrosol solution) or the negative control(vehicle alone was given 10 ml/kg body weight) was administered 30 min.(p.o.) before the test meal at doses calculated to be 3-fold, 10-fold or30-fold the ED₅₀ found in efficacy studies in the rat.

Dose 3-fold ED₅₀ Dose 10-fold ED₅₀ Dose 30-fold ED₅₀ [mg/kg body [mg/kgbody [mg/kg body Compound weight p.o.] weight p.o.] weight p.o.] Example1 1.0 3.0 10.0 (ED₅₀ = 0.31 mg/kg BW) Example 2 0.3 1.0 3.0 (ED₅₀ = 0.1mg/kg BW)

The test meal (suspension of 7.5 g barium sulfate in 10 ml salt-freewater) is given orally by gavage at a dose of 2 ml/100 g body weight.Thirty minutes after the administration of the test meal the animalswere killed in deep isoflurane anaesthesia by cervical dislocation. Thestomach and the intestine were then exposed by laparatomy and removed.

The removed stomach was weighed, then incised, the contents removed andthe empty stomach is weighed again.

The length of gut traversed with barium sulfate in relation to the wholelength of the gut is determined by direct measurements using a ruler.

Evaluation of Gastric Emptying

The gastric content was calculated from the weight difference betweenthe filled and empty stomach and normalized to 100 g body weight. Thus,an increase in weight difference indicated an impaired gastric emptying,whereas a decrease in weight difference indicated an enhanced gastricemptying.

Evaluation of Intestinal Transit

The length of gut traversed with barium sulphate (as judged by visualinspection) in relation to the whole length of the gut (from the pylorusto the rectum) is determined by direct measurements using a ruler.

Intestinal transit is calculated as the percentage movement of bariumsulphate in the intestine in relation to the whole length of the gut.Consequently an increased intestinal transit length indicated anaccelerated intestinal transit whereas a decreased intestinal transitlength indicated decelerated intestinal transit.

Statistics

Data are expressed as mean±standard deviation (SD). For each dose,comparisons were performed using an analysis of variance (ANOVA) and apost hoc Dunnett test to compare the various groups to the controls whenthe ANOVA was significant. p<0.05 was considered significant.

Consequently the compounds of the invention show no statisticallyrelevant gastrointestinal side effects, even at doses which are up tothe 30-fold ED₅₀-dosis, because as shown in FIGS. 1 a and b and 2 a andb rats which had received either example 1 or 2 neither showed asubstantially enhanced or impaired gastric emptying nor a substantiallyaccelerated or decelerated intestinal transit even at doses up to30-fold ED₅₀-dose.

For Example 1 the gastric emptying shows no relevant differences at a3-fold ED₅₀ dose and at a 10-fold ED₅₀ dose, and only a very moderateenhancement of the weight difference per body weight at a 30-fold ED₅₀dose. However, the intestinal transits for the corresponding animalswhich received Example compound 1 showed no significant differencescompared to those intestinal transits of the negative controls even upto the 30-fold ED₅₀ dose.

For Example 2 both the gastric emptying and the intestinal transitshowed no relevant differences compared to the negative control duringall tested doses of Example compound 2, not even at the 30-fold ED₅₀dose.

Consequently the compounds of the invention are not only more potentwith respect to PDE4B inhibition than the compounds disclosed in WO2009/050248 (as shown in Experiments 1.1 and 1.2), but also show norelevant gastrointestinal side effects.

6. INDICATIONS

The compounds of formula I have a broad potential in differenttherapeutic fields. Particular mention should be made of thoseapplications for which the compounds according to the invention offormula I are preferably suited on account of their pharmaceuticalefficacy as PDE4 inhibitors. Examples include respiratory orgastrointestinal diseases or complaints, inflammatory diseases of thejoints, skin or eyes, cancers, and also diseases of the peripheral orcentral nervous system.

Particular mention should be made of the prevention and treatment ofdiseases of the airways and of the lung which are accompanied byincreased mucus production, inflammations and/or obstructive diseases ofthe airways. Examples include acute, allergic or chronic bronchitis,chronic obstructive bronchitis (COPD), coughing, pulmonary emphysema,allergic or non-allergic rhinitis or sinusitis, chronic rhinitis orsinusitis, asthma, alveolitis, Farmer's disease, hyperreactive airways,infectious bronchitis or pneumonitis, paediatric asthma, bronchiectases,pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome),bronchial oedema, pulmonary oedema, bronchitis, pneumonia orinterstitial pneumonia triggered by various causes, such as aspiration,inhalation of toxic gases, or bronchitis, pneumonia or interstitialpneumonia as a result of heart failure, irradiation, chemotherapy,cystic fibrosis or mucoviscidosis, or alpha1-antitrypsin deficiency.

Also deserving special mention is the treatment of inflammatory diseasesof the gastrointestinal tract. Examples include acute or chronicinflammatory changes in gall bladder inflammation, Crohn's disease,ulcerative colitis, inflammatory pseudopolyps, juvenile polyps, colitiscystica profunda, pneumatosis cystoides intestinales, diseases of thebile duct and gall bladder, e.g. gallstones and conglomerates,inflammatory diseases of the joints such as rheumatoid arthritis orinflammatory diseases of the skin and eyes.

Preferential mention should also be made to the treatment ofsarcoidosis.

Preferential mention should also be made of the treatment of cancers.Examples include all forms of acute and chronic leukaemias such as acutelymphatic and acute myeloid leukaemia, chronic lymphatic and chronicmyeloid leukaemia as well as bone tumours such as e.g. osteosarcoma andall kinds of gliomas such as e.g. oligodendroglioma and glioblastoma.

Preferential mention should also be made of the prevention and treatmentof diseases of the peripheral or central nervous system. Examples ofthese include depression, bipolar or manic depression, acute and chronicanxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease,acute and chronic multiple sclerosis or acute and chronic pain as wellas injuries to the brain caused by stroke, hypoxia or craniocerebraltrauma.

Particularly preferably the present invention relates to the use ofcompounds of formula I for preparing a pharmaceutical composition forthe treatment of inflammatory or obstructive diseases of the upper andlower respiratory tract including the lungs, such as for exampleallergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis,idiopathic pulmonary fibrosis, fibrosing alveolitis, COPD, chronicbronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerativecolitis, alpha-1-antitrypsin deficiency, particularly COPD, chronicbronchitis and asthma.

It is most preferable to use the compounds of formula I for thetreatment of inflammatory and obstructive diseases such as COPD, chronicbronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerativecolitis, rheumatoid arthritis, particularly COPD, chronic bronchitis andasthma.

It is also preferable to use the compounds of formula I for thetreatment of diseases of the peripheral or central nervous system suchas depression, bipolar or manic depression, acute and chronic anxietystates, schizophrenia, Alzheimer's disease, Parkinson's disease, acuteand chronic multiple sclerosis or acute and chronic pain as well asinjuries to the brain caused by stroke, hypoxia or craniocerebraltrauma.

It is also preferable to use the compounds of formula I for thetreatment of inflammatory diseases of the eyes, in particular for thetreatment of the “dry eyes” syndrome and for the treatment of glaucoma.Individuals with the “dry eyes” syndrome suffer from ocular discomfort(dry, gritty feeling; itching; stinging/burning; pain/soreness) andblurred vision. The phosphodiesterase 4 (PDE4) enzymes regulate thebiological processes of a host by degrading the second messenger cAMP.PDE4 inhibitors have been intensively investigated as antiinflammatorytherapies because increases in cAMP levels are known to attentuateinflammatoy responses in multiple cell types (see Govek et al,Bioorganic & Med. Chem. Lett 20, (2010), pp. 2928-2932).

Furthermore it is also preferable to use the compounds of formula I forthe treatment of diseases of the eyes, in particular for the treatmentof glaucoma, since it has been shown that an increase in cAMP protectsretinal ganglion cells from high intracellular pressure (IOP) inducedcell death (see Seki T. et al, J Mol Neurosci. 2011 January;43(1):30-4.), and an increase in cAMP is involved in the reduction ofIOP (see Naveh N. et al., Br J Ophthalmol. 2000 December;84(12):1411-4), the main reason for the development of glaucoma.

7. COMBINATIONS

The compounds of formula I may be used on their own or in conjunctionwith other active substances of formula I according to the invention. Ifdesired the compounds of formula I may also be used in combination withother pharmacologically active substances. It is preferable to use forthis purpose active substances selected for example from amongbetamimetics, anticholinergics, corticosteroids, other PDE4-inhibitors,LTD4-antagonists, EGFR-inhibitors, MRP4-inhibitors, dopamine agonists,H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors, NSAIDS,COX 2 inhibitors, EP 4-receptor antagonists, DPP4-inhibitors or doubleor triple combinations thereof, such as for example combinations ofcompounds of formula I with one or two compounds selected from among

-   -   EP 4-receptor antagonists, DPP4 inhibitors, NSAIDS, COX 2        inhibitors and corticosteroids,    -   betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors        and LTD4-antagonists,    -   anticholinergics, betamimetics, corticosteroids,        PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists,    -   PDE4-inhibitors, corticosteroids, EGFR-inhibitors and        LTD4-antagonists    -   EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists    -   EGFR-inhibitors and LTD4-antagonists    -   CCR3-inhibitors, iNOS-inhibitors (inducible nitric oxide        synthase-inhibitors), (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin        (hereinafter referred to as “BH4”) and the derivatives thereof        as mentioned in WO 2006/120176 and SYK-inhibitors (spleen        tyrosine kinase inhibitors)    -   anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors        and MRP4-inhibitors. The invention also relates to combinations        of three active substances, each chosen from one of the        above-mentioned categories of compounds.

Suitable betamimetics used are preferably compounds selected from amongalbuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol,fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmeterol, salmefamol, soterenol, sulphonterol,tiaramide, terbutaline, tolubuterol, CHF-1035, HOKU-81, KUL-1248,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide,5-[2-(5.6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxyl)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1.4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-aceticacid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3.4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyricacid,8-{2-[2-(3.4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-oneand1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol,optionally in the form of the racemates, enantiomers, diastereomers andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates or hydrates thereof.

According to the invention the acid addition salts of the betamimeticsare preferably selected from among the hydrochloride, hydrobromide,hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably the hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.Of the above-mentioned acid addition salts the salts of hydrochloricacid, methanesulphonic acid, benzoic acid and acetic acid areparticularly preferred according to the invention.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, oxitropium salts, flutropium salts, ipratropiumsalts, glycopyrronium salts, trospium salts, tropenol2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionatemethobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide,tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol3,3′,4,4′-tetrafluorobenzilate methobromide, scopine3,3′,4,4′-tetrafluorobenzilate methobromide, tropenol4,4′-difluorobenzilate methobromide, scopine 4,4′-difluorobenzilatemethobromide, tropenol 3,3′-difluorobenzilate methobromide, -scopine3,3′-difluorobenzilate methobromide, tropenol9-hydroxy-fluorene-9-carboxylate-methobromide, tropenol9-fluoro-fluorene-9-carboxylate-methobromide, scopine9-hydroxy-fluoren-9-carboxylate methobromide, scopine9-fluoro-fluorene-9-carboxylate methobromide, tropenol9-methyl-fluorene-9-carboxylate methobromide, scopine9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropinebenzilate methobromide, cyclopropyltropine 2,2-diphenylpropionatemethobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylatemethobromide, cyclopropyltropine 9-methyl-xanthene-9-carboxylatemethobromide, cyclopropyltropine 9-hydroxy-fluorene-9-carboxylatemethobromide, methyl-cyclopropyltropine 4,4′-difluorobenzilatemethobromide, tropenol 9-hydroxy-xanthene-9-carboxylate-methobromide,scopine 9-hydroxy-xanthene-9-carboxylate methobromide, tropenol9-methyl-xanthene-9-carboxylate methobromide, scopine9-methyl-xanthene-9-carboxylate methobromide, tropenol9-ethyl-xanthene-9-carboxylate methobromide, tropenol9-difluoromethyl-xanthene-9-carboxylate methobromide, scopine9-hydroxymethyl-xanthene-9-carboxylate methobromide, optionally in theform of the solvates or hydrates thereof.

In the above-mentioned salts the cations tiotropium, oxitropium,flutropium, ipratropium, glycopyrronium and trospium are thepharmacologically active ingredients. As anions, the above-mentionedsalts may preferably contain chloride, bromide, iodide, sulphate,phosphate, methanesulphonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate,while chloride, bromide, iodide, sulphate, methanesulphonate orp-toluenesulphonate are preferred as counter-ions. Of all the salts, thechlorides, bromides, iodides and methanesulphonate are particularlypreferred.

Of particular importance is tiotropium bromide. In the case oftiotropium bromide the pharmaceutical combinations according to theinvention preferably contain it in the form of the crystallinetiotropium bromide monohydrate, which is known from WO 02/30928. If thetiotropium bromide is used in anhydrous form in the pharmaceuticalcombinations according to the invention, it is preferable to useanhydrous crystalline tiotropium bromide, which is known from WO03/000265.

Corticosteroids used here are preferably compounds selected from amongprednisolone, prednisone, butixocortpropionate, flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort,RPR-106541, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionateand (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Particularly preferred is the steroid selected from among flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionateand (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers or diastereomersthereof and optionally in the form of the salts and derivatives,solvates and/or hydrates thereof.

Any reference to steroids includes a reference to any salts orderivatives, hydrates or solvates thereof which may exist. Examples ofpossible salts and derivatives of the steroids may be: alkali metalsalts, such as for example sodium or potassium salts, sulfobenzoates,phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates thereof.

Other PDE4 inhibitors which may be used are preferably compoundsselected from among enprofyllin, theophyllin, roflumilast, ariflo(cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram,D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418,PD-168787, T-440, T-2585, V-11294A, C1-1018, CDC-801, CDC-3052, D-22888,YM-58997,Z-15370,N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,(−)p-[(4aR*.10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1.6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N—[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,(S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridineand9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers or diastereomersand optionally in the form of the pharmacologically acceptable acidaddition salts, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theabove-mentioned PDE4-inhibitors might be in a position to form aremeant, for example, salts selected from among the hydrochloride,hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate,hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferablyhydrochloride, hydrobromide, hydrosulphate, hydrophosphate,hydrofumarate and hydromethanesulphonate.

EP 4 receptor antagonists which may be used are preferably compoundsselected from among

-   [N-{[4-(5,9-diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinoline-7yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide];-   5-butyl-2,4-dihydro-4-[[2′-[N-(3-methyl-2-thiophene-carbonyl)sulfamoyl]biphenyl-4-yl]methyl]-2-[(2-trifluoromethyl)phenyl]-1,2,4-triazole-3-on;-   (4-{(1S)-1-[({5-chloro-2-[(4-fluorophenyl)oxy]phenyl}carbonyl)amino]ethyl}benzoic    acid;-   N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)    carbonyl]-4-methylbenzol sulfonamide;-   4-[[4-(5-methoxy-2-pyridinyl)phenoxy]methyl]-5-methyl-N-[(2-methylphenyl)sulfonyl]-2-furane    carboxamide;-   11alpha,    15alpha-dihydroxy-16-(3-methoxymethylphenyl)-9-oxo-17,18,19,20-tetranor-5-thia-13(E)    prostanoic acid methyl ester;-   4-cyano-2-[[2-(4-fluoro-1-naphthalenyl)-1-oxopropyl]amino]-benzene    butyric acid and-   N-{2-[4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetyl}benzene    sulphonamide.

NSAIDS which may be used are preferably compounds selected from amongAceclofenac, Acemetacin, Acetylsalicylsaure, Alclofenac, Alminoprofen,Amfenac, Ampiroxicam, Antolmetinguacil, Anirolac, Antrafenin,Azapropazon, Benorilat, Bermoprofen, Bindarit, Bromfenac, Bucloxinsáure,Bucolom, Bufexamac, Bumadizon, Butibufen, Butixirat, Carbasalatcalcium,Carprofen, Cholin Magnesium Trisalicylat, Celecoxib, Cinmetacin,Cinnoxicam, Clidanac, Clobuzarit, Deboxamet, Dexibuprofen,Dexketoprofen, Diclofenac, Diflunisal, Droxicam, Eltenac,Enfenaminsáure, Etersalat, Etodolac, Etofenamat, Etoricoxib, Feclobuzon,Felbinac, Fenbufen, Fenclofenac, Fenoprofen, Fentiazac, Fepradinol,Feprazon, Flobufen, Floctafenin, Flufenaminsáure, Flufenisal,Flunoxaprofen, Flurbiprofen, Flurbiprofenaxetil, Furofenac, Furprofen,Glucametacin, Ibufenac, Ibuprofen, Indobufen, Indometacin,Indometacinfarnesil, Indoprofen, Isoxepac, Isoxicam, Ketoprofen,Ketorolac, Lobenzarit, Lonazolac, Lomoxicam, Loxoprofen, Lumiracoxib,Meclofenaminsáure, Meclofen, Mefenaminsáure, Meloxicam, Mesalazin,Miroprofen, Mofezolac, Nabumeton, Naproxen, Nifluminsáure, Olsalazin,Oxaprozin, Oxipinac, Oxyphenbutazon, Parecoxib, Phenylbutazon,Pelubiprofen, Pimeprofen, Pirazolac, Priroxicam, Pirprofen, Pranoprofen,Prifelon, Prinomod, Proglumetacin, Proquazon, Protizininsáure,Rofecoxib, Romazarit, Salicylamid, Salicylsaure, Salmistein, Salnacedin,Salsalat, Sulindac, Sudoxicam, Suprofen, Talniflumat, Tenidap, Tenosal,Tenoxicam, Tepoxalin, Tiaprofensaure, Taramid, Tilnoprofenarbamel,Timegadin, Tinoridin, Tiopinac, Tolfenaminsáure, Tolmetin, Ufenamat,Valdecoxib, Ximoprofen, Zaltoprofen and Zoliprofen.

COX2-inhibitors (Coxibe) which may be used are preferably compoundsselected from among Celecoxib, Meloxicam, Etoricoxib, Lumiracoxib,Parecoxib, Rofecoxib and Valdecoxib.

LTD4-antagonists which may be used are preferably compounds selectedfrom among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523),MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321,1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-aceticacid,1-(((1(R)-3(3-(2-(2.3-dichlorothieno[3,2-b]pyridin-5-yl-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-aceticacid and[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]aceticacid, optionally in the form of the racemates, enantiomers ordiastereomers, optionally in the form of the pharmacologicallyacceptable acid addition salts and optionally in the form of the saltsand derivatives, solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theLTD4-antagonists may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.By salts or derivatives which the LTD4-antagonists may be capable offorming are meant, for example: alkali metal salts, such as, forexample, sodium or potassium salts, alkaline earth metal salts,sulphobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogen phosphates, palmitates, pivalates or furoates.

The EGFR-inhibitors used are preferably compounds selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclopropylmethoxy-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}-amino)-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline,4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline,4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline,4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline,cetuximab, trastuzumab, ABX-EGF and Mab ICR-62, optionally in the formof the racemates, enantiomers or diastereomers thereof, optionally inthe form of the pharmacologically acceptable acid addition saltsthereof, the solvates and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theEGFR-inhibitors may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate andhydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide,hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.

Examples of dopamine agonists which may be used preferably includecompounds selected from among bromocriptine, cabergoline,alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol,ropinirol, talipexol, terguride and viozan. Any reference to theabove-mentioned dopamine agonists within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts and optionally hydrates thereof which may exist. By thephysiologically acceptable acid addition salts which may be formed bythe above-mentioned dopamine agonists are meant, for example,pharmaceutically acceptable salts which are selected from the salts ofhydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid and maleic acid.

Examples of H1-antihistamines preferably include compounds selected fromamong epinastine, cetirizine, azelastine, fexofenadine, levocabastine,loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine,bamipin, cexchlorpheniramine, pheniramine, doxylamine,chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine,ebastine, desloratidine and meclozine. Any reference to theabove-mentioned H1-antihistamines within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts which may exist.

Examples of PAF-antagonists preferably include compounds selected fromamong4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines,6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines.

MRP4-inhibitors used are preferably compounds selected from amongN-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac,dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulphate,dilazep, dinitrophenyl-s-glutathione, estradiol 17-beta-glucuronide,estradiol 3,17-disulphate, estradiol 3-glucuronide, estradiol3-sulphate, estrone 3-sulphate, flurbiprofen, folate,N5-formyl-tetrahydrofolate, glycocholate, clycolithocholic acidsulphate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholicacid sulphate, methotrexate, MK571((E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoicacid), alpha-naphthyl-beta-D-glucuronide, nitrobenzyl mercaptopurineriboside, probenecid, PSC833, sildenafil, sulfinpyrazone,taurochenodeoxycholate, taurocholate, taurodeoxycholate,taurolithocholate, taurolithocholic acid sulphate, topotecan, trequinsinand zaprinast, dipyridamole, optionally in the form of the racemates,enantiomers, diastereomers and the pharmacologically acceptable acidaddition salts and hydrates thereof.

By acid addition salts with pharmacologically acceptable acids aremeant, for example, salts selected from among the hydrochlorides,hydrobromides, hydroiodides, hydrosulphates, hydrophosphates,hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates,hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates,hydrooxalates, hydrosuccinates, hydrobenzoates andhydro-p-toluenesulphonates, preferably the hydrochlorides,hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates andhydromethanesulphonates.

Compounds which may be used as iNOS inhibitors are compounds selectedfrom among: S-(2-aminoethyl)isothiourea, aminoguanidine,2-aminomethylpyridine, AMT, L-canavanine, 2-iminopiperidine,S-isopropylisothiourea, S-methylisothiourea, S-ethylisothiourea,S-methyltiocitrullin, S-ethylthiocitrulline, L-NA(N^(•)-nitro-L-arginine), L-NAME (N^(•)-nitro-L-argininemethylester),L-NMMA (N^(G)-monomethyl-L-arginine), L-NIO(N^(•)-iminoethyl-L-ornithine), L-NIL (N^(•)-iminoethyl-lysine),(S)-6-acetimidoylamino-2-amino-hexanoic acid (1H-tetrazol-5-yl)-amide(SC-51) (J. Med. Chem. 2002, 45, 1686-1689), 1400W,(S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-butyric acid(GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600),2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine(BYK191023) (Mol. Pharmacol. 2006, 69, 328-337),2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO01/62704),2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-6-tifluoromethyl-nicotinonitrile(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-benzonitrile(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-benzonitrile(WO 2004/041794),(2S.4R)-2-amino-4-(2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol-5-yl-butan-1-ol(WO 2004/041794),2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-nicotinonitrile(WO 2004/041794),4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy-nicotinonitrile(WO 02/090332), substituted 3-phenyl-3,4-dihydro-1-isoquinolinamine suchas e.g. AR-C102222 (J. Med. Chem. 2003, 46, 913-916),(1S.5S.6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine(ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667),(4R,5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med. Chem.2004, 12, 4101), (4R,5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine(Bioorg. Med. Chem. Lett. 2005, 15, 1361), 4-aminotetrahydrobiopterine(Curr. Drug Metabol. 2002, 3, 119-121),(E)-3-(4-chloro-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidin-1-yl]-ethylcarbamoyl}-2-pyridin-2-yl-ethyl)-acrylamide(FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76),3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine(PPA250) (J. Pharmacol. Exp. Ther. 2002, 303, 52-57), methyl3-{[(benzo[1,3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-pyrimidin-4-yl)-piperazine-1-carboxylate(BBS-1) (Drugs Future 2004, 29, 45-52),(R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-carboxylicacid (2-benzo[1,3]dioxol-5-yl-ethyl)-amide (BBS-2) (Drugs Future 2004,29, 45-52) and the pharmaceutical salts, prodrugs or solvates thereof.

Examples of iNOS-inhibitors within the scope of the present inventionmay also include antisense oligonucleotides, particularly thoseantisense oligonucleotides which bind iNOS-coding nucleic acids. Forexample, WO 01/52902 describes antisense oligonucleotides, particularlyantisense oligonucleotides, which bind iNOS coding nucleic acids, formodulating the expression of iNOS. iNOS-antisense oligonucleotides asdescribed particularly in WO 01/52902 may therefore also be combinedwith the PDE4-inhibitors of the present invention on account of theirsimilar effect to the iNOS-inhibitors.

Compounds which may be used as SYK-inhibitors are preferably compoundsselected from among:

-   2-[(2-aminoethyl)amino]-4-[(3-bromophenyl)amino]-5-pyrimidinecarboxamide;-   2-[[7-(3,4-dimethoxyphenyl)imidazo[1,2-c]pyrimidin-5-yl]amino]-3-pyridinecarboxamide;-   6-[[5-fluoro-2-[3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one;-   N-[3-bromo-7-(4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine    7-(4-methoxyphenyl)-N-methyl-1,6-naphthyridin-5-amine;-   N-[7-(4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(2-thienyl)-1,6-naphthyridin-5-yl-1,3-propanediamine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,2-ethanediamine;-   N-[7-(4-methoxyphenyl)-2-(trifluoromethyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4-methoxyphenyl)-3-phenyl-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-(7-phenyl-1,6-naphthyridin-5-yl)-1,3-propanediamine;-   N-[7-(3-fluorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3-chlorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[3-(trifluoromethoxy)phenyl]-1,6-naphthyridin-5yl]-1,3-propanediamine;-   N-[7-(4-fluorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4-fluorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4-chlorophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4′-methyl[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-1,3-propanediamine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4-bromophenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(4-methylphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(methylthio)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(1-methylethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   7-[4-(dimethylamino)phenyl]-N-methyl-1,6-naphthyridin-5-amine;-   7-[4-(dimethylamino)phenyl]-N,N-dimethyl-1,6-naphthyridin-5-amine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,4-butanediamine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,5-pentanediamine;-   3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]oxy]-1-propanol;-   4-[5-(4-aminobutoxy)-1,6-naphthyridin-7-yl]-N,N-dimethyl-benzenamine;-   4-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]-1-butanol;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-N-methyl-1,3-propanediamine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-N-methyl-1,3-propanediamine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-N,N′-dimethyl-1,3-propanediamine;-   1-amino-3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]-2-propanol;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-2,2-dimethyl-1,3-propanediamine;-   7-[4-(dimethylamino)phenyl]-N-(3-pyridinylmethyl)-1,6-naphthyridin-5-amine;-   N-[(2-aminophenyl)methyl]-7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-amine;-   N-[7-[6-(dimethylamino)    [1,1′-biphenyl]-3-yl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[3-chloro-4-(diethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(diethylamino)phenyl]-3-methyl-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3′-fluoro[1,1′-biphenyl]-3-yl)-1,6-naphthyridin-5-yl]-1,2-ethanediamine,-   N-[7-(4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,6-naphthyridine-1,3-propanediamine;-   N,N′-bis(3-aminopropyl)-7-(4-methoxyphenyl)-2,5-diamine;-   N-[7-(4-methoxyphenyl)-2-(phenylmethoxy)-1,6-naphthyridin-5-yl]-1,6-naphthyridine-1,3-propanediamine;-   N5-(3-aminopropyl)-7-(4-methoxyphenyl)-N2-(phenylmethyl)-2,5-diamine;-   N-[7-(2-naphthalenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(T-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3,4-dimethylphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   1-amino-3-[[7-(2-naphthalenyl)-1,6-naphthyridin-5-yl]amino]-2-propanol;-   1-amino-3-[[7-(2′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]amino]-2-propanol;-   1-amino-3-[[7-(4′-methoxy[1,    1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]amino]-2-propanol;-   1-amino-3-[[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridin-5-yl]amino]-2-propanol;-   1-amino-3-[[7-(4-bromophenyl)-1,6-naphthyridin-5-yl]amino]-2-propanol;-   N-[7-(4′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-2,2-dimethyl-1,3-propanediamine;-   1-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]-2-propanol;-   2-[[2-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]ethyl]thio]-ethanol;-   7-[4-(dimethylamino)phenyl]-N-(3-methyl-5-isoxazolyl)-1,6-naphthyridin-5-amine;-   7-[4-(dimethylamino)phenyl]-N-4-pyrimidinyl-1,6-naphthyridin-5-amine;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-cyclohexanediamine;-   N,N-dimethyl-4-[5-(1-piperazinyl)-1,6-naphthyridin-7-yl]-benzenamine;-   4-[5-(2-methoxyethoxy)-1,6-naphthyridin-7-yl]-N,N-dimethyl-benzenamine;-   1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-4-piperidinol;-   1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-3-pyrrolidinol;-   7-[4-(dimethylamino)phenyl]-N-(2-furanylmethyl)-1,6-naphthyridin-5-amine;-   7-[4-(dimethylamino)phenyl]-N-[3-(1H-imidazol-1-yl)propyl]-1,6-naphthyridin-5-amine;-   1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-4-piperidinecarboxamide;-   1-[3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]amino]propyl]-2-pyrrolidinone;-   N-[3′-[5-[(3-aminopropyl)amino]-1,6-naphthyridin-7-yl][1,1′-biphenyl]-3-yl]-acetamide;-   N-[7-(4′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[4′-[5-[(3-aminopropyl)amino]-1,6-naphthyridin-7-yl][1,1′-biphenyl]-3-yl]-acetamide;-   N-[7-[4-(1,3-benzodioxol-5-yl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(2-thienyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-fluoro-3-(trifluoromethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(3-pyridinyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(1,3-benzodioxol-5-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(6-methoxy-2-naphthalenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   7-[4-(dimethylamino)phenyl]-N-(4-pyridinylmethyl)-1,6-naphthyridin-5-amine;-   3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]methylamino]-propanenitrile;-   7-[4-(dimethylamino)phenyl]-N-[1-(phenylmethyl)-4-piperidinyl]-1,6-naphthyridin-5-amine;-   (1R.2S)—N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,2-cyclohexanediamine,-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,2-benzenedimethanamine;-   N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,4-butanediamine;-   N-[7-[3′.5′-bis(trifluoromethyl)    [1,1′-biphenyl]-4-yl]-1,6-naphthyridin-5-yl]0.3-propanediamine;-   N-[7-(3′-methoxy[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3′-fluoro[1,1′-biphenyl]-4-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   4-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]oxy]-1-butanol;-   N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   7-[4-(dimethylamino)phenyl]-N-(2.2.6.6-tetramethyl-4-piperidinyl)-1,6-naphthyridin-5-amine;-   N-[7-[3-bromo-4-(dimethylamino)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(1-methyl-1H-indol-5-yl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[3-(trifluoromethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-(trifluoromethyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-(3-bromo-4-methoxyphenyl)-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N-[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,4-cyclohexanediamine;-   4-[[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]oxy]-cyclohexanol;-   N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridin-5-yl]-1,3-propanediamine;-   N,N-dimethyl-4-[5-(4-methyl-1-piperazinyl)-1,6-naphthyridin-7-yl]-benzenamine;-   4-[[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]oxy]-cyclohexanol;-   N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridin-5-yl]-1,4-butanediamine;-   1,1-dimethylethyl    [3-[[5-[(3-aminopropyl)amino]-7-(4-methoxyphenyl)-1,6-naphthyridin-2-yl]amino]propyl]-carbamate.

The invention further relates to pharmaceutical preparations whichcontain a triple combination comprising a compound of formula I, II orIII and two further active agents, both independently from one anotherselected from the above-mentioned groups of active agents such asanother PDE4B-inhibitor, an anticholinergic, a betamimetic, acorticosteroid, an EGFR-inhibitor, a MRP4-inhibitor, an LTD4-antagonist,an iNOS-inhibitor, a PAF-antagonist, a H1-antihistamine, dopaminagonist, SYK inhibitor. The invention further refers to the preparationof such a double or triple combination and the use thereof for treatingrespiratory complaints.

8. FORMULATIONS

Suitable forms for administration are for example tablets, capsules,solutions, syrups, emulsions or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e. in amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g. a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised bythe content of one or more compounds of formula I according to thepreferred embodiments above.

It is particularly preferable if the compounds of formula I areadministered orally, and it is also particularly preferable if they areadministered once or twice a day. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample inert diluents such as calcium carbonate, calcium phosphate orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talcand/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. aflavouring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.petroleum fractions), vegetable oils (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silicic acid andsilicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers(e g lignin, spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. Magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulphate and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavour enhancers or colourings in addition to the excipients mentionedabove.

It is also preferred if the compounds of formula I are administered byinhalation, particularly preferably if they are administered once ortwice a day. For this purpose, the compounds of formula I have to bemade available in forms suitable for inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions, which are optionally present inadmixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

Inhalable Powders

If the active substances of formula I are present in admixture withphysiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare the inhalable powdersaccording to the invention: monosaccharides (e.g. glucose or arabinose),disaccharides (e.g. lactose, saccharose, maltose), oligo- andpolysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol,xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures ofthese excipients with one another. Preferably, mono- or disaccharidesare used, while the use of lactose or glucose is preferred,particularly, but not exclusively, in the form of their hydrates. Forthe purposes of the invention, lactose is the particularly preferredexcipient, while lactose monohydrate is most particularly preferred.Methods of preparing the inhalable powders according to the invention bygrinding and micronising and by finally mixing the components togetherare known from the prior art.

Propellant-Containing Inhalable Aerosols

The propellant-containing inhalable aerosols which may be used accordingto the invention may contain the compounds of formula I dissolved in thepropellant gas or in dispersed form. The propellant gases which may beused to prepare the inhalation aerosols according to the invention areknown from the prior art. Suitable propellant gases are selected fromamong hydrocarbons such as n-propane, n-butane or isobutane andhalohydrocarbons such as preferably fluorinated derivatives of methane,ethane, propane, butane, cyclopropane or cyclobutane. The propellantgases mentioned above may be used on their own or in mixtures thereof.Particularly preferred propellant gases are fluorinated alkanederivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227(1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. Thepropellant-driven inhalation aerosols used within the scope of the useaccording to the invention may also contain other ingredients such asco-solvents, stabilisers, surfactants, antioxidants, lubricants and pHadjusters. All these ingredients are known in the art.

Propellant-Free Inhalable Solutions

The compounds of formula I according to the invention are preferablyused to prepare propellant-free inhalable solutions and inhalablesuspensions. Solvents used for this purpose include aqueous oralcoholic, preferably ethanolic solutions. The solvent may be water onits own or a mixture of water and ethanol. The solutions or suspensionsare adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.The pH may be adjusted using acids selected from inorganic or organicacids. Examples of particularly suitable inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/orphosphoric acid. Examples of particularly suitable organic acids includeascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,succinic acid, fumaric acid, acetic acid, formic acid and/or propionicacid etc. Preferred inorganic acids are hydrochloric and sulphuricacids. It is also possible to use the acids which have already formed anacid addition salt with one of the active substances. Of the organicacids, ascorbic acid, fumaric acid and citric acid are preferred. Ifdesired, mixtures of the above acids may also be used, particularly inthe case of acids which have other properties in addition to theiracidifying qualities, e.g. as flavourings, antioxidants or complexingagents, such as citric acid or ascorbic acid, for example. According tothe invention, it is particularly preferred to use hydrochloric acid toadjust the pH.

Co-solvents and/or other excipients may be added to the propellant-freeinhalable solutions used for the purpose according to the invention.Preferred co-solvents are those which contain hydroxyl groups or otherpolar groups, e.g. alcohols—particularly isopropyl alcohol,glycols—particularly propyleneglycol, polyethyleneglycol,polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyvinylpyrrolidone, otherstabilisers, complexing agents, antioxidants and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavourings, vitamins and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas sodium chloride as isotonic agents. The preferred excipients includeantioxidants such as ascorbic acid, for example, provided that it hasnot already been used to adjust the pH, vitamin A, vitamin E,tocopherols and similar vitamins or provitamins occurring in the humanbody. Preservatives may be used to protect the formulation fromcontamination with pathogens. Suitable preservatives are those which areknown in the art, particularly cetyl pyridinium chloride, benzalkoniumchloride or benzoic acid or benzoates such as sodium benzoate in theconcentration known from the prior art.

For the treatment forms described above, ready-to-use packs of amedicament for the treatment of respiratory complaints are provided,containing an enclosed description including for example the wordsrespiratory disease, COPD or asthma, together withdihydrothienopyrimidine and one or more combination partners selectedfrom those described above.

The invention claimed is:
 1. A method of making compound C

wherein HX is tosylic acid, hydrochloric acid, or sulphuric acid, themethod comprising: A) first contacting 4-cyano-piperidine with an acidand then reacting with ammonia in order to obtain intermediate E

B) reacting intermediate E with compound D in the presence of a base

and C) adding the acid HX to obtain compound C.
 2. The method of claim1, wherein the acid in step A) is hydrochloric acid.
 3. The method ofclaim 1, wherein the base in step B) is sodium methanolate.